Inhibitory chimeric receptor architecture

Abstract

Provided herein are inhibitory chimeric antigen receptor compositions and cells comprising such compositions. Also provided are methods of using the inhibitory chimeric antigen receptors and cells.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 369,480, filed July 26, 2022, the entire disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0002] Sequence Listing This application contains an electronically submitted Sequence Listing, which is hereby incorporated by reference in its entirety. Said XML copy a was created on XX / 20XX, is named XXXXXUS_sequencelisting.xml, and is X,XXX,XXX bytes in size. [Background technology]

[0003] background Chimeric antigen receptors (CARs) enable the targeted activation of immune regulatory cells, such as T cells, in vivo. These recombinant membrane receptors possess an antigen-binding domain and one or more signaling domains (e.g., T cell activation domains). These specialized receptors enable T cells to recognize specific protein antigens on tumor cells and induce T cell activation and signaling pathways. Recent clinical trials using chimeric receptor-expressing T cells have provided compelling support for their utility as cancer immunotherapy agents. However, despite these promising results, several side effects associated with CAR T cell therapy have been identified, raising serious safety concerns. One of these side effects is "on-target, off-target" adverse events resulting from TCR-CAR-engineered T cells, in which CAR T cells bind their ligands and induce immune responses outside of the target tumor tissue. Therefore, the ability to identify appropriate CAR targets is crucial for effectively targeting and treating tumors without damaging normal cells expressing the same target antigen.

[0004] Inhibitory chimeric antigen receptors (also known as iCARs) are protein constructs that inhibit or reduce immunoregulatory cell activity after binding to their cognate ligands on target cells. Current iCARs leverage the PD-1 intracellular domain for inhibition, but this has proven difficult to recapitulate. Therefore, alternative inhibitory domains for use in iCARs are needed. Summary of the Invention

[0005] overview One embodiment of the present disclosure provides a polypeptide comprising: an extracellular protein binding domain; a transmembrane domain, wherein the transmembrane domain is operably linked to the extracellular protein binding domain; and one or more intracellular signaling domains, wherein the one or more intracellular signaling domains are operably linked to the transmembrane domain, and wherein the one or more intracellular signaling domains are each selected from the group consisting of MPZL1, IRTA1, LIR8, PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, and the like. , LIFR, ERMAP, IL1RAPL2, CDH5, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM, wherein at least one of the one or more intracellular signaling domains is capable of preventing, attenuating, or inhibiting activation of the tumor-targeting chimeric receptor expressed on an immune-modulating cell.

[0006] In some embodiments, the transmembrane domain is derived from the same protein as one of the one or more intracellular signaling domains, and optionally the transmembrane domain further comprises at least a portion of the extracellular domain of the same protein, or the transmembrane domain is derived from a first protein and the one or more intracellular signaling domains are derived from a different protein than the first protein.

[0007] In some embodiments, one of the one or more intracellular signaling domains is derived from PECAM-1, and optionally, one of the one or more intracellular signaling domains is at least about 80%, at least about 85%, at least about 90%, at least about 100%, or at least about 110% identical to KCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEANSHYGHNDDVRNHAMKPINDNKEPLNSDVQYTEVQVSSAESHKDLGKKDTETVYSEVRKAVPDAVESRYSRTEGSLDGT (SEQ ID NO: 1). 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical, and optionally one of the one or more intracellular signaling domains is KCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEANSHYGHNDDVRNHAMKPINDNKEPLNSDVQYTEVQVSSAESHKDLGKKDTETVYSEVRKAVPDAVE SRYSRTEGSLDGT (SEQ ID NO: 1), wherein one of the one or more intracellular signaling domains is derived from CD72, and optionally, one of the one or more intracellular signaling domains is at least about 80%, at least about 85%, at least about 90%, at least about 91%, or at least about 100% identical to MAEAITYADLRFVKAPLKKSISSRLGQDPGADDDGEITYENVQVPAVLGVPSSLASSVLGDKAAVKSEQPTASWRAVTSPAVGRILPCRTTCLRY (SEQ ID NO: 2). and optionally, one of the one or more intracellular signaling domains comprises the amino acid sequence MAEAITYADLRFVKAPLKKSISSRLGQDPGADDDGEITYENVQVPAVLGVPSSLASSVLGDKAAVKSEQPTASWRAVTSPAVGRILPCRTTCLRY (SEQ ID NO: 2);One of the one or more intracellular signaling domains is derived from IRTA2, and optionally, one of the one or more intracellular signaling domains is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, or at least about 94% identical to LSRKAGRKPASDPARSPSDSDSQEPTYHNVPAWEELQPVYTNANPRGENVVYSEVRIIQEKKKHAVASDPRHLRNKGSPIIYSEVKVASTPVSGSLFLASSAPHR (SEQ ID NO: 3). and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence of LSRKAGRKPASDPARSPSDSDSQEPTYHNVPAWEELQPVYTNANPRGENVVYSEVRIIQEKKKHAVASDPRHLRNKGSPIIYSEVKVASTPVSGSLFLASSAPHR (SEQ ID NO: 3), and wherein the one or more intracellular signaling domains comprise an amino acid sequence that is about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to one of the one or more intracellular signaling domains. and optionally, one of the one or more intracellular signaling domains is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, or at least about 97% identical to HKISGESSATNEPRGASRPNPQEFTYSSPTPDMEELQPVYVNVGSVDVDVVYSQVWSMQQPESSANIRTLLENKDSQVIYSSVKKS (SEQ ID NO: 4). and optionally, the intracellular signaling domain comprises the amino acid sequence of HKISGESSATNEPRGASRPNPQEFTYSSPTPDMEELQPVYVNVGSVDVDVVYSQVWSMQQPESSANIRTLLENKDSQVIYSSVKKS (SEQ ID NO: 4), and optionally, one of the one or more intracellular signaling domains is derived from NKIR, and optionally, one of the one or more intracellular signaling domains isWRMMKYQQKAAGMSPEQVLQPLEGDLCYADLTLQLAGTSPQKATTKLSSAQVDQVEVEYVTMASLPKEDISYASLTLGAEDQEPTYCNMGHLSSHLPGRGPEEPTEYSTISRP (SEQ ID NO: 5), and optionally one of the one or more intracellular signaling domains comprises the amino acid sequence of WRMMKYQQKAAGMSPEQVLQPLEGDLCYADLTLQLAGTSPQKATTKLSSAQVDQVEVEYVTMASLPKEDISYASLTLGAEDQEPTYCNMGHLSSHLPGRGPEEPTEYSTISRP (SEQ ID NO: 5), and one or more is derived from IL1RAP; and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to YRAHFGTDETILDGKEYDIYVSYARNAEEEEFVLLTLRGVLENEFGYKLCIFDRDSLPGGIVTDETLSFIQKSRRLLVVLSPNYVLQGTQALLELKAGLENMASRGNINVILVQYKAVKETKVKELKRAKTVLTVIKWKGEKSKYPQGRFWKQLQVAMPVKKSPRRSSSDEQGLSYSSLKNV (SEQ ID NO: 6); and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to YRAHFGTDETILDGKEYDIYVSYARNAEEEEFVLLTLRGVLENEFGYKLCIFDRDSLPGGIVTDETLSFIQKSRRLLVVLSPNYVLQGTQALLELKAGLENMASRGNINVILVQYKAVKETKVKELKRAKTVLTVIKWKGEKSKYPQGRFWKQLQVAMPVKKSPRRSSSDEQGLSYSSLKNV (SEQ ID NO: 6).YRAHFGTDETILDGKEYDIYVSYARNAEEEEFVLLTLRGVLENEFGYKLCIFDRDSLPGGIVTDETLSFIQKSRRLLVVLSPNYVLQGTQALLELKAGLENMASRGNINVILVQYKAVKETKVKELKRAKTVLTVIKWKGEKSKYPQGRFWKQLQVAMPVKKSPRRSSSDEQGLSYSSLKNV (SEQ ID NO: 6), wherein one of the one or more intracellular signaling domains is derived from PTPRO, and optionally one of the one or more intracellular signaling domains is , at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to EGADYINANYIPGYNSPQEYIATQGPLPETRNDFWKMVLQQKSQIIVMLTQCNEKRRVKCDHYWPFTEEPIAYGDITVEMISEEEQDDWACRHFRINYADEMQDVMHFNYTAWPDHGVPTANAAESILQFVHMVRQQATKSKGPMIIHCSAGVGRTGTFIALDRLLQHIRDHEFVDILGLVSEMRSYRMSMVQTEEQYIFIHQCVQLMWMKKKQQFCISDVIYENVSKS (SEQ ID NO: 7), and optionally one of the one or more intracellular signaling domains isLRKKHLQMARECGAGTFVNFASLERDGKLPYNWRRSIFAFLTLLPSCLWTDYLLAFYINPWSKNGLKKRKLTNPVQLDDFDAYIKDMAKDSDYKFSLQFEELKLIGLDIPHFAAD LPLNRCKNRYTNILPYDFSRVRLVSMNEEEGADYINANYIPGYNSPQEYIATQGPLPETRNDFWKMVLQQKSQIIVMLTQCNEKRRVKCDHYWPFTEEPIAYGDITVEMISEEEQ DDWACRHFRINYADEMQDVMHFNYTAWPDHGVPTANAAESILQFVHMVRQQATKSKGPMIIHCSAGVGRTGTFIALDRLLQHIRDHEFVDILGLVSEMRSYRMSMVQTEEQYIFIHQCVQLMWMKKKQQFCISDVIYENVSKS (SEQ ID NO: 7), wherein one of the one or more intracellular signaling domains is derived from PTPRZ1; and optionally, one of the one or more intracellular signaling domains is(SEQ ID NO:8), and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to (SEQ ID NO:8), and optionally, one of the one or more intracellular signaling domains comprises(SEQ ID NO:8), wherein one of the one or more intracellular signaling domains is derived from TLT1, and optionally one of the one or more intracellular signaling domains is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%,or about 100% identical, optionally one of the one or more intracellular signaling domains comprises the amino acid sequence of MAKRKQGNRLGVCGRFLSSRVSGMNPSSVVHHVSDSGPAAELPLDVPHIRLDSPPSFDNTTYTSLPLDSPSGKPSLPAPSSLPPLPPKVLVCSKPVTYATVIFPGGNKGGGTSCGPAQNPPNNQTPSS (SEQ ID NO: 9), wherein one of the one or more intracellular signaling domains is derived from SLAMF1, and optionally One of the one or more intracellular signaling domains is an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to QLRRRGKTNHYQTTVEKKSLTIYAQVQKPGPLQKKLDSFPAQDPCTTIYVAATEPVPESVQETNSITVYASVTLPES (SEQ ID NO: 10). and optionally one of the one or more intracellular signaling domains comprises the amino acid sequence of QLRRRGKTNHYQTTVEKKSLTIYAQVQKPGPLQKKLDSFPAQDPCTTIYVAATEPVPESVQETNSITVYASVTLPES (SEQ ID NO: 10), and one of the one or more intracellular signaling domains is derived from SLAMF5, and optionally one of the one or more intracellular signaling domains comprises the amino acid sequence of RLFKRRQGRIFPEGSCLNTFTKNPYAASKKTIYTYIMA SRNTQPAESRIYDEILQSKVLPSKEEPVNTVYSEVQFADKMGKASTQDSKPPGTSSYEIVI (SEQ ID NO: 11), and optionally one of the one or more intracellular signaling domains comprises an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SRNTQPAESRIYDEILQSKVLPSKEEPVNTVYSEVQFADKMGKASTQDSKPPGTSSYEIVI (SEQ ID NO: 11), and optionally one of the one or more intracellular signaling domains isRLFKRRQGRIFPEGSCLNTFTKNPYAASKKTIYTYIMASRNTQPAESRIYDEILQSKVLPSKEEPVNTVYSEVQFADKMGKASTQDSKPPGTSSYEIVI (SEQ ID NO: 11), wherein one of the one or more intracellular signaling domains is derived from PCDHGC3; and optionally, one of the one or more intracellular signaling domains is FKVYKWKQSRDLYRAPVSSLYRTPGPSLHADAVRGGLMSPHLYHQVYLTTDSRRSDPLLKK; PGAASPLASRQNTLRSCDPVFYRQVLGAESAPPGQQAPPNTDWRFSQAQRPGTSGSQNGDDTGTWPNNQFDTEMLQAMILASASEAADGSSTLGGGAGTMGLSARYGPQFTLQHVPDYRQNVYIPGSNATLTNAAGKRDGKAPAGGNGNKKKSGKKEKK (SEQ ID NO: 95) and at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, and optionally one of the one or more intracellular signaling domains is FKVYKWKQSRDLYRAPVSSLYRTPGPSLHADAVRGGLMSPHLYHQVYLTTDSRRSDPLLKKPGAASPLASRQNTLRSCDPVFYRQVLGAESAPPGQQAPPNTDWRFSQAQRPGTSGSQNGDDTGTWPNNQFDTEMLQAMILASASEAADGSSTLG GGAGTMGLSARYGPQFTLQHVPDYRQNVYIPGSNATLTNAAGKRDGKAPAGGNGNKKKSGKKEKK (SEQ ID NO: 95), wherein one of the one or more intracellular signaling domains is derived from LIFR, and optionally, one of the one or more intracellular signaling domains is YRKREWIKETFYPDIPNPENCKALQFQKSVCEGSSALKTLEMNPCTPNNVEVLETRSAFPKIEDTEIISPVAERPEDRSDAEPENHVVVSYCPPIIEE EIPNPAADEAGGTAQVIYIDVQSMYQPQAKPEEEQENDPVGGAGYKPQMHLPINSTVEDIAAEEDLDKTAGYRPQANVNTWNLVSPDSPRSIDSNSEIVSFGSPCSINSRQFLIPPKDEDSPKSNGGGWSFTNFFQNKPND (SEQ ID NO: 96) and at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%,an amino acid sequence at least about 98%, at least about 99%, or about 100% identical, and optionally one of the one or more intracellular signaling domains comprises the amino acid sequence of: YRKREWIKETFYPDIPNPENCKALQFQKSVCEGSSALKTLEMNPCTPNNVEVLETRSAFPKIEDTEIISPVAERPEDRSDAEPENHVVVSYCPPIIEEEIPNPAADEAGGTAQVIYIDVQSMYQPQAKPEEEQENDPVGGAGYKPQMHLPINSTVEDIAAEEDLDKTAGYRPQANVNTWNLVSPDSPRSIDSNSEIVSFGSPCSINSRQFLIPPKDEDSPKSNGGGWSFTNFFQNKPND (SEQ ID NO: 96), and one of the one or more intracellular signaling domains is derived from ERMAP, and optionally one of the one or more intracellular signaling domains is WKQRRAKEKLLYEHVTEVDNLLSDHAKEKGKLHKAVKKLR SELKLKRAAANSGWRRARLHFVAVTLDPDTAHPKLILSEDQRCVRLGDRRQPVPDNPQRFDFVVSILGSEYFTTGCHYWEVYVGDKTKWILGVCSESVSRKGKVTASPANG HWLLRQSRGNEYEALTSPQTSFRLKEPPRCVGIFLDYEAGVISFYNVTNKSHIFTFTHNFSGPLRPFFEPCLHDGGKNTAPLVICSELHKSEESIVPRPEGKGHANGDVSL KVNSSLLPPKAPELKDIILSLPPDLGPALQELKAPSF (SEQ ID NO: 97), and optionally one of the one or more intracellular signaling domains comprises an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to KVNSSLLPPKAPELKDIILSLPPDLGPALQELKAPSF (SEQ ID NO: 97), and optionally one of the one or more intracellular signaling domains comprisesand optionally, one of the one or more intracellular signaling domains is derived from IL1RAPL2; and optionally, one of the one or more intracellular signaling domains is derived from IL1RAPL2. EVLPDVLEKHYGYKLFIPERDLIPSGTYMEDLTRYVEQSRRLIIVLTPDYILRRGWSIFELESRLHNMLVSGEIKVILIECTELKGKVNCQEVESLKRSIKLLSLIKWKG SKSSKLNSKFWKHLVYEMPIKKKEMLPRCHVLDSAEQGLFGELQPIPSIAMTSTSATLVSSQADLPEFHPSDSMQIRHCCRGYKHEIPATTLPVPSLGNHHTYCNLPLTLL NGQLPLNNTLKDTQEFHRNSSLLPLSSKELSFTSDIW (SEQ ID NO:98), and optionally one of the one or more intracellular signaling domains comprises an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to NGQLPLNNTLKDTQEFHRNSSLLPLSSKELSFTSDIW (SEQ ID NO:98), and optionally one of the one or more intracellular signaling domains comprisesKCYNIELMLFYRQHFGADETNDDNKEYDAYLSYTKVDQDTLDCDNPEEEQFALEVLPDVLEKHYGYKLFIPERDLIPSGTYMEDLTRYVEQSRRLIIVLTPDYILRRGWSIFELESRLHNMLVS GEIKVILIECTELKGKVNCQEVESLKRSIKLLSLIKWKGSKSSKLNSKFWKHLVYEMPIKKKEEMLPRCHVLDSAEQGLFGELQPIPSIAMTSTSATLVSSQADLPEFHPSDSMQIRHCCGYKHE IPATTLPVPSLGNHHTYCNLPLTLLNGQLPLNNTLKDTQEFHRNSSLLPLSSKELSFTSDIW (SEQ ID NO: 98), wherein one of the one or more intracellular signaling domains is derived from CDH5, and optionally one of the one or more intracellular signaling domains is RRRLRKQARAHGKSVPEIHEQLVTYDEEGGGEMDTTSYDVSVLNSVRRGGAKPPRPALDARPSLYAQVQKPPRHAPGAHGGPGEMAAMIEVKKDEADHDGD GPPYDTLHIYGYEGSESIAESLSSLGTDSSDSDVDYDFLNDWGPRFKMLAELYGSDPREELLY (SEQ ID NO: 99), and optionally, one of the one or more intracellular signaling domains is RR RLRKQARAHGKSVPEIHEQLVTYDEEGGGEMDTTSYDVSVLNSVRRGGAKPPRPALDARPSLYAQVQKPPRHAPGAHGGPGEMAAMIEVKKDEADHDGDGPPYDTLHIYGYEGSESIAESLSSLGTDSSDSDVDYDFLNDWGPRFKMLAELYGSDPREELLY (SEQ ID NO: 99), wherein one of the one or more intracellular signaling domains is derived from MPZL1; and optionally, one of the one or more intracellular signaling domains isSMILAVLYRRKNSKRDYTGCSTSESLSPVKQAPRKSPSDTEGLVKSLPSGSHQGPVIYAQLDHSGGHHSDKINKSESVVYADIRKN (SEQ ID NO: 100), and optionally, one or more one of the above intracellular signaling domains comprises the amino acid sequence SMILAVLYRRKNSKRDYTGCSTSESLSPVKQAPRKSPSDTEGLVKSLPSGSHQGPVIYAQLDHSGGHHSDKINKSESVVYADIRKN (SEQ ID NO: 100), and one of the one or more intracellular signaling domains is derived from MPZ; and optionally, one of the one or more intracellular signaling domains comprises the amino acid sequence RYCWLRRQAALQRRLSAMEKGKLHKPGKDASKRGRQTPVLYAMLDHSRSTKAVS EKKAKGLGESRKDKK (SEQ ID NO: 101), and optionally one of the one or more intracellular signaling domains is RYCWLRRQAALQRRLSAMEKGKLHKPGKDASKRGRQTPVLYAMLDHSRS TKAVSEKKAKGLGESRKDKK (SEQ ID NO: 101), wherein one of the one or more intracellular signaling domains is derived from FCGR2B, and optionally one of the one or more intracellular signaling domains is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, orand optionally, one of the one or more intracellular signaling domains comprises the amino acid sequence of VVALIYCRKKRISALPGYPECREMGETLPEKPANPTNPDEADKVGAENTITYSLLMHPDALEEPDDQNRI (SEQ ID NO: 102), wherein one of the one or more intracellular signaling domains is derived from SIGLEC-6; and optionally, Optionally, one of the one or more intracellular signaling domains is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or identical to RVKTRRKKAAQPVQNTDDVNPVMVSGSRGHQHQFQTGIVSDHPAEAGPISEDEQELHYAVLHFHKVQPQEPKVTDTEYSEIKIHK (SEQ ID NO: 103). or about 100% identical, optionally one of the one or more intracellular signaling domains comprises the amino acid sequence of RVKTRRKKAAQPVQNTDDVNPVMVSGSRGHQHQFQTGIVSDHPAEAGPISEDEQELHYAVLHFHKVQPQEPKVTDTEYSEIKIHK (SEQ ID NO: 103), and optionally one of the one or more intracellular signaling domains is derived from MPIG6B, and optionally one of the one or more intracellular signaling domains is WLHRRLPPQPIRPLPRF APLVKTEPQRPVKEEEPKIPGDLDQEPSLLYADLDHLALSRPRRLSTADPADASTIYAVVV (SEQ ID NO: 104), and optionally one of the one or more intracellular signaling domains comprises an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to APLVKTEPQRPVKEEEPKIPGDLDQEPSLLYADLDHLALSRPRRLSTADPADASTIYAVVV (SEQ ID NO: 104), and optionally one of the one or more intracellular signaling domains comprisesWLHRRLPPQPIRPLPRFAPLVKTEPQRPVKEEEPKIPGDLDQEPSLLYADLDHLALSRPRRLSTADPADASTIYAVVV (SEQ ID NO: 104), wherein one of the one or more intracellular signaling domains is derived from VSIG4, and optionally, one of the one or more intracellular signaling domains is MLCRKTSQQEHVYEAARAHAREANDSGETMRVAIFASGCSSDEPTSQNLGNNYSDEPCIGQ EYQIIAQINGNYARLLDTVPLDYEFLATEGKSVC (SEQ ID NO: 105), and optionally, one of the one or more intracellular signaling domains is MLCRKTSQQ EHVYEAARAHAREANDSGETMRVAIFASGCSSDEPTSQNLGNNYSDEPCIGQEYQIIAQINGNYARLLDTVPLDYEFLATEGKSVC (SEQ ID NO: 105), wherein one of the one or more intracellular signaling domains is derived from SIGLEC-12, and optionally, one of the one or more intracellular signaling domains is RSCRKKSARPAVGVGDTGMEDANAVRGSASQGPLIESPADDSPPHHAPPA LATPSPEEGEIQYASLSFHKARPQYPQEQEAIGYEYSEINIPK (SEQ ID NO: 106), and optionally one of the one or more intracellular signaling domains comprises an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LATPSPEEGEIQYASLSFHKARPQYPQEQEAIGYEYSEINIPK (SEQ ID NO: 106), and optionally one of the one or more intracellular signaling domains comprisesRSCRKKSARPAVGVGDTGMEDANAVRGSASQGPLIESPADDSPPHHAPPALATPSPEEGEIQYASLSFHKARPQYPQEQEAIGYEYSEINIPK (SEQ ID NO: 106), wherein one of the one or more intracellular signaling domains is derived from LIR8; and optionally, one of the one or more intracellular signaling domains is RHRHQSKHRTSAHFYRPAGAAGPEPKDQGLQKRASPVADIQEEILNAAVKDTQPKDGVEMDAPAAASEAPQDVTYAQLHSLTLRREATEP; RHRHQSKHRTSAHFYRPAGAAGPEPKDQGLQKRASPVADIQEEILNAAVKDTQPKDGVEMDAPAAASEAPQDVTYAQLHSLTLRREATEPPPSQEREPPAEPSIYAPLAIH (SEQ ID NO: 107), and optionally one of the one or more intracellular signaling domains comprises the amino acid sequence of RHRHQSKHRTSAHFYRPAGAAGPEPKDQGLQKRASPVADIQEEILNAAVKDTQPKDGVEMDAPAAASEAPQDVTYAQLHSLTLRREATEPPPSQEREPPAEPSIYAPLAIH (SEQ ID NO: 107), and optionally one of the one or more intracellular signaling domains is derived from IRTA1, and optionally one of the one or more intracellular signaling domains is derived from IRTA1 YVDVHPKKGDLVYSEIQTTQLGEEEEANTSRTLLEDKDVSVVYSEVKTQHPDNSAGKISSKDEES (SEQ ID NO: 108), and optionally an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to YVDVHPKKGDLVYSEIQTTQLGEEEEANTSRTLLEDKDVSVVYSEVKTQHPDNSAGKISSKDEES (SEQ ID NO: 108), wherein one of the one or more intracellular signaling domains comprises the amino acid sequence of HCWRRRKSGVGFLGDETRLPPAPGPGESSHSICPAQVELQSLYVDVHPKKGDLVYSEIQTTQLGEEEEANTSRTLLEDKDVSVVYSEVKTQHPDNSAGKISSKDEES (SEQ ID NO: 108), and one of the one or more intracellular signaling domains is derived from KIR2DL4; and optionally, one of the one or more intracellular signaling domains comprises the amino acid sequence ofRWCSKKKDAAVMNQEPAGHRTVNREDSDEQDPQEVTYAQLDHCIFTQRKITGPSQRSKRPSTDTSVCIELPNAEPRALSPAHEHHSQALMGSSRETTALSQTQLASSNVPAAGI (SEQ ID NO: 109), or at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or and optionally, one of the one or more intracellular signaling domains comprises the amino acid sequence of RWCSKKKDAAVMNQEPAGHRTVNREDSDEQDPQEVTYAQLDHCIFTQRKITGPSQRSKRPSTDTSVCIELPNAEPRALSPAHEHHSQALMGSSRETTALSQTQLASSNVPAAGI (SEQ ID NO: 109), wherein one of the one or more intracellular signaling domains is derived from KIR2DL5, and optionally, the one or more intracellular signaling domains comprise the amino acid sequence of RWCSKKKDAAVMNQEPAGHRTVNREDSDEQDPQEVTYAQLDHCIFTQRKITGPSQRSKRPSTDTSVCIELPNAEPRALSPAHEHHSQALMGSSRETTALSQTQLASSNVPAAGI (SEQ ID NO: 109). One of the main amino acids is LHCCCSNKKNAAVMDQEPAGDRTVNREDSDDQDPQEVTYAQLDHCVFTQTKITSPSQRPKTPPTDTTMYMELPNAKPRSLSPAHKHHSQALRGSSRETTALSQNRVASSHVPAAGI (SEQ ID NO: 110) and at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, an amino acid sequence at least about 99%, or about 100%, identical to one of the one or more intracellular signaling domains, and optionally one of the one or more intracellular signaling domains comprises the amino acid sequence of LHCCCSNKKNAAVMDQEPAGDRTVNREDSDDQDPQEVTYAQLDHCVFTQTKITSPSQRPKTPPTDTTMYMELPNAKPRSLSPAHKHHSQALRGSSRETTALSQNRVASSHVPAAGI (SEQ ID NO: 110), wherein one of the one or more intracellular signaling domains is derived from SIGLEC-7, and optionallyone of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to RSCRKKSARPAADVGDIGMKDANTIRGSASQGNLTESWADDNPRHHGLAAHSSGEEREIQYAPLSFHKGEPQDLSGQEATNNEYSEIKIPK (SEQ ID NO: 111), optionally, one of the one or more intracellular signaling domains comprises the amino acid sequence of RSCRKKSARPAADVGDIGMKDANTIRGSASQGNLTESWADDNPRHHGLAAHSSGEEREIQYAPLSFHKGEPQDLSGQEATNNEYSEIKIPK (SEQ ID NO: 111); One of the one or more intracellular signaling domains is derived from FCRH3, and optionally, one of the one or more intracellular signaling domains is at least about 80%, at least about 85%, at least about 90%, or at least about 95% identical to HYARARRKPGGLSATGTSSHSPSECQEPSSSRPSRIDPQEPTHSKPLAPMELEPMYSNVNPGDSNPIYSQIWSIQHTKENSANCPMMHQEHEELTVLYSELKKTHPDDSAGEASSRGRAHEEDDEENYENVPRVLLASDH (SEQ ID NO: 112). 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the one or more intracellular signaling domains of SELKKTHPDDSAGEASSRGRAHEEDDEENYENVPRVLLASDH (SEQ ID NO: 112), wherein one of the one or more intracellular signaling domains is derived from PCDHGC5, and optionally, one of the one or more intracellular signaling domains is KCLQGNADGDGGGGQCCRRQDSPSPDFYKQSSPNLQVSSDGTLKYMEVTLRPTDSQSHCYRTCFSPASDGSDFTFLRPLSVQQPTALALEPDAIRSRSNTLRERSQQAPPNTD WRFSQAQRPGTSGSQNGDDTGTWPNNQFDTEMLQAMILASASEAADGSSTLGGGAGTMGLSARYGPQFTLQHVPDYRQNVYIPGSNATLTNAAGKRDGKAPAGGNGNKKKSGKKEKK (SEQ ID NO: 113) and at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%,or an amino acid sequence that is about 100% identical, and optionally one of the one or more intracellular signaling domains is KCLQGNADGDGGGGQCCRRQDSPSPDFYKQSSPNLQVSSDGTLKYMEVTLRPTDSQSHCYRTCFSPASDGSDFTFLRPLSVQQPTALALEPDAIRSRSNTLRERSQQAPPNTDWRFSQAQRPGTSGSQNGDDTGTWPNNQFDTEMLQAMILASASEAADGSSTLGGGAGTMGLSARYGPQFTLQ HVPDYRQNVYIPGSNATLTNAAGKRDGKAPAGGNGNKKKSGKKEKK (SEQ ID NO: 113), wherein one of the one or more intracellular signaling domains is derived from CDH11, and optionally one of the one or more intracellular signaling domains is RRQKKEPLIVFEEEDVRENIITYDDEGGGEEDTEAFDIATLQNPDGINGFIPRKDIKPEYQYMPRPGLRPAPNSVDVDDFINTRIQEADNDPTAPPYDSIQIYGYE GRGSVAGSLSSLESATTDSDLDYDYLQNWGPRFKKLADLYGSKDTFDDDS (SEQ ID NO: 114), and optionally one of the one or more intracellular signaling domains is RRQK KEPLIVFEEEDVRENIITYDDEGGGEEDTEAFDIATLQNPDGINGFIPRKDIKPEYQYMPRPGLRPAPNSVDVDDFINTRIQEADNDPTAPPYDSIQIYGYEGRGSVAGSLSSLESATTDSDLDYDYLQNWGPRFKKLADLYGSKDTFDDDS (SEQ ID NO: 114), wherein one of the one or more intracellular signaling domains is derived from IMPG2; and optionally, one of the one or more intracellular signaling domains isYFFIRTLQAHHDRSERESPFSGSSRQPDSLSSIENAVKYNPVYESHRAGCEKYEGPYPQHPFYSSASGDVIGGLSREEIRQMYESSELSREEIQERMRVLELYANDPEFAAFVREQQVEEV (SEQ ID NO: 115) and at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, 9%, or about 100% identical, and optionally one of the one or more intracellular signaling domains comprises the amino acid sequence of YFFIRTLQAHHDRSERESPFSGSSRQPDSLSSIENAVKYNPVYESHRAGCEKYEGPYPQHPFYSSASGDVIGGLSREEIRQMYESSELSREEIQERMRVLELYANDPEFAAFVREQQVEEV (SEQ ID NO: 115), and one of the one or more intracellular signaling domains is derived from DSCAM, and optionally one or more One of the intracellular signaling domains is RRRRREQRLKRLRDAKSLAEMLMSKNTRTSDTLSKQQQTLRMHIDIPRAQLLIEERDTMETIDDRSTVLLTDADFGEAAKQKSLTVTHTVHYQSVSQATGPLVDVSDARPGTNPTTRRNAKAGPTARNRYASQWTLNRPHPTISAHTLTTDWRLPTPRAAGSVDKESDSYSVSPSQDTDRARSSMVSTESASSTYEELARAYEHAKMEEQLRHAKFTITECFISDTS SEQLTAGTNEYTDSLTSSTPSESGICRFTASPPKPQDGGRVMNMAVPKAHRPGDLIHLPPYLRMDFLLNRGGPGTSRDLSLGQACLEPQKSRTLKRPTVLEPIPMEAASSASSTREGQSWQPGAVATLPQREGAELGQAAKMSSSQESLLDSRGHLKGNNPYAKSYTLV (SEQ ID NO: 116) and at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%,and optionally one of the one or more intracellular signaling domains is RRRREQRLKRLRDAKSLAEMLMSKNTRTSDTLSKQQQTLRMHIDIPRAQLLIEERDTMETIDDRSTVLLTDADFGEAAKQKSLTVTHTVHYQSVSQATGPLVDVSDARPGTNPTTRRNAKAGPTARNRYASQWTLNRPHPTISAHTLTTDWRLP It contains the amino acid sequence of TPRAAGSVDKESDSYSVSPSQDTDRARSSMVSTESASSTYEELARAYEHAKMEEQLRHAKFTITECFISDTSSEQLTAGTNEYTDSLTSSTPSESGICRFTASPKPQDGGRVMNMAVPKAHRPGDLIHLPPYLRMDFLLNRGGPGTSRDLSLGQACLEPQKSRTLKRPTVLEPIPMEAASSASSTREGQSWQPGAVATLPQREGAELGQAAKMSSSQESLLDSRGHLKGNNPYAKSYTLV (SEQ ID NO: 116).

[0008] Another embodiment of the present disclosure provides a chimeric inhibitory receptor comprising: an extracellular protein binding domain; a transmembrane domain, wherein the transmembrane domain is operably linked to the extracellular protein binding domain; and one or more intracellular signaling domains, wherein the one or more intracellular signaling domains are operably linked to the transmembrane domain, wherein at least one of the one or more intracellular signaling domains comprises at least one immunoreceptor tyrosine-dependent switch motif (ITSM), or at least one ITIM and at least one phosphatase, and wherein at least one of the one or more intracellular signaling domains is capable of preventing, attenuating, or inhibiting activation of a tumor-targeting chimeric receptor expressed on an immunomodulatory cell.

[0009] In some embodiments, the chimeric inhibitory receptor comprises at least one ITIM and at least one phosphatase, optionally the phosphatase is a protein tyrosine phosphatase (PTP), and optionally the one or more intracellular signaling domains are each derived from a protein selected from the group consisting of PTPRO and PTPRZ1, and optionally one of the one or more intracellular signaling domains is derived from PTPRO, and optionally the intracellular signaling domain is selected from the group consisting of LRKKHLQMARECGAGTFVNFASLERDGKLPYNWRRSIFAFLTLLPSCLWTDYLLAFYINPWSKNGLKKRKLTNPVQLDDFDAYIKDMAKDSDYKFSLQFEELKLIGLDIPHFAADLPLNRCKNRYTNILPYDFSRVRLVSMNEEEGADYINANYIPGYN SPQEYIATQGPLPETRNDFWKMVLQQKSQIIVMLTQCNEKRRVKCDHYWPFTEEPIAYGDITVEMISEEEQDDWACRHFRINYADEMQDVMHFNYTAWPDHGVPTANAAESILQFVHMVRQQATKSKGPMIIHCSAGVGRTGTFIALDRLLQHIRDHEFVDILGLVSEMRSYRMSMVQTEEQYIFIHQCVQLMWMKKKQQFCISDVIYENVSKS (SEQ ID NO: 7), and optionally the intracellular signaling domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical toLRKKHLQMARECGAGTFVNFASLERDGKLPYNWRRSIFAFLTLLPSCLWTDYLLAFYINPWSKNGLKKRKLTNPVQLDDFDAYIKDMAKDSDYKFSLQFEELKLIGLDIPHFA ADLPLNRCKNRYTNILPYDFSRVRLVSMNEEEGADYINANYIPGYNSPQEYIATQGPLPETRNDFWKMVLQQKSQIIVMLTQCNEKRRVKCDHYWPFTEEPIAYGDITVEMISE EEQDDWACRHFRINYADEMQDVMHFNYTAWPDHGVPTANAAESILQFVHMVRQQATKSKGPMIIHCSAGVGRTGTFIALDRLLQHIRDHEFVDILGLVSEMRSYRMSMVQTEEQYIFIHQCVQLMWMKKKQQFCISDVIYENVSKS (SEQ ID NO: 7), or wherein one of the one or more intracellular signaling domains is derived from PTPRZ1, and optionally the intracellular signaling domain is(SEQ ID NO: 8), and optionally the intracellular signaling domain comprises an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to(SEQ ID NO: 8)

[0010] In some embodiments, a chimeric inhibitory receptor comprises at least one ITSM, and optionally, the one or more intracellular signaling domains are each derived from a protein selected from the group consisting of SLAMF1 and SLAMF5, and optionally, one of the one or more intracellular signaling domains is derived from SLAMF1, and optionally, the intracellular signaling domain is 97%, at least about 98%, at least about 99%, or about 100% identical to TLPES (SEQ ID NO: 10), and optionally, the intracellular signaling domain is or one of the one or more intracellular signaling domains is derived from SLAMF5, and optionally the intracellular signaling domain is at least about 80%, at least about 85%, at least about 90%, at least about 91%, or identical to RLFKRRQGRIFPEGSCLNTFTKNPYAASKKTIYTYIMASRNTQPAESRIYDEILQSKVLPSKEEPVNTVYSEVQFADKMGKASTQDSKPPGTSSYEIVI (SEQ ID NO: 11). and an amino acid sequence that is at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical, and optionally, the intracellular signaling domain comprises the amino acid sequence of RLFKRRQGRIFPEGSCLNTFTKNPYAASKKTIYTYIMASRNTQPAESRIYDEILQSKVLPSKEEPVNTVYSEVQFADKMGKASTQDSKPPGTSSYEIVI (SEQ ID NO: 11).

[0011] In some embodiments, the transmembrane domain is selected from the group consisting of CD8, CD28, CD3ζ, CD4, 4-IBB, OX40, ICOS, 2B4, CD25, CD7, LAX, LAT, LIR1, PCAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4 , KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM, and optionally the chimeric inhibitory receptor comprises a transmembrane domain derived from PECAM-1, and optionally the transmembrane domain has at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 100%, at least about 101%, at least about 102%, at least about 103%, at least about 104%, at least about 105%, at least about 106%, at least about 107%, at least about 108%, at least about 109%, at least about 110%, at least about 111%, at least about 112%, at least about 113%, at least about 114%, at least about 115%, at least about 116%, at least about 117%, at least about 118%, at least about 119%, at least about 120%, at least about 121%, at least about 122%, at least about 123%, at least about 124%, at least about 125%, at least about 126%, at least about 127%, at least about 128%, at least about 129%, at least about 130%, at least about 131%, at least about 132 and the chimeric inhibitory receptor comprises an amino acid sequence that is at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence of GLIAVIIGVIIALLIIAA (SEQ ID NO: 24), and the chimeric inhibitory receptor comprises a transmembrane domain derived from LIR1, and optionally the transmembrane domain is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% identical to an amino acid sequence of VIGILVAVILLLLLLLLLFLI (SEQ ID NO: 25). and the chimeric inhibitory receptor comprises an amino acid sequence that is at least about 4%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VAGGLLSIAGLAAGALLLYCW (SEQ ID NO: 26), and optionally the transmembrane domain comprises the amino acid sequence of VIGILVAVILLLLLLLLLFLI (SEQ ID NO: 25), and the chimeric inhibitory receptor comprises a transmembrane domain derived from IRTA2, and optionally the transmembrane domain is at least about 80%, at least about 85%, at least about 90%, at least about 91%, to VAGGLLSIAGLAAGALLLYCW (SEQ ID NO: 26),and the chimeric inhibitory receptor comprises an amino acid sequence that is at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LWGLFGVLGFTGVALLLYALF (SEQ ID NO: 27), and optionally the transmembrane domain comprises the amino acid sequence of VAGGLLSIAGLAAGALLLYCW (SEQ ID NO: 26), and the chimeric inhibitory receptor comprises a transmembrane domain derived from IRTA4, and optionally the transmembrane domain is at least about 80%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LWGLFGVLGFTGVALLLYALF (SEQ ID NO: 27). and the chimeric inhibitory receptor comprises an amino acid sequence that is about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to any of the chimeric inhibitory receptors, and optionally the transmembrane domain comprises the amino acid sequence of LWGLFGVLGFTGVALLLYALF (SEQ ID NO: 27), and the chimeric inhibitory receptor comprises a transmembrane domain derived from NKIR, and optionally the transmembrane domain is VLLPLIFTILLLLLVAA SLLA (SEQ ID NO:28), and optionally the transmembrane domain comprises the amino acid sequence of VLLPLIFTILLLLLVAASLLA (SEQ ID NO:28), and the chimeric inhibitory receptor comprises a transmembrane domain derived from IL1RAP, and optionally and optionally, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VLLVVILIVVYHVYWLEMVLF (SEQ ID NO: 29), and the chimeric inhibitory receptor isand a transmembrane domain derived from PTPRO, optionally wherein the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to ISVLAILSTLLIGLLLVTLII (SEQ ID NO: 30). 30), wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from PTPRZ1, and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to AVIPLVIVSALTFICLVVLVGILIYW (SEQ ID NO: 31), and optionally , the transmembrane domain comprises the amino acid sequence of AVIPLVIVSALTFICLVVLVGILIYW (SEQ ID NO: 31), and the chimeric inhibitory receptor comprises a transmembrane domain derived from TLT1, and optionally the transmembrane domain is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 100%, at least about 101%, at least about 102%, at least about 103%, at least about 104%, at least about 105%, at least about 106%, at least about 107%, at least about 108%, at least about 109%, at least about 110%, at least about 111%, at least about 112%, at least about 113%, at least about 114%, at least about 115%, at least about 116%, at least about 117%, at least about 118%, at least about 119%, at least about 120%, at least about 121%, at least about 122%, at least about 123%, at least about 124%, at least about 125%, at least about 126%, at least about 127%, at least about 128%, at least about 129%, at least about 130%, at least about 131%, at least about 132 %, or about 100% identical to WAVYAGLLGGVIMILIMVVIL (SEQ ID NO: 33), optionally wherein the transmembrane domain comprises the amino acid sequence of LIWGAVLLVGLLVAAVVLFAV (SEQ ID NO: 32), and the chimeric inhibitory receptor comprises a transmembrane domain derived from SLAMF1, optionally wherein the transmembrane domain is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%,and wherein the chimeric inhibitory receptor comprises an amino acid sequence that is at least about 97%, at least about 98%, at least about 99%, or about 100% identical to a chimeric inhibitory receptor, and optionally the transmembrane domain comprises the amino acid sequence of WAVYAGLLGGVIMILIMVVIL (SEQ ID NO: 33), and the chimeric inhibitory receptor comprises a transmembrane domain derived from SLAMF5, and optionally the transmembrane domain is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, to a chimeric inhibitory receptor ... and the chimeric inhibitory receptor comprises an amino acid sequence that is at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LLSVLAMFFLLVLILSSVFLF (SEQ ID NO: 34), and the chimeric inhibitory receptor comprises a transmembrane domain derived from PCDHGC3, and optionally the transmembrane domain is at least about 80%, at least about 85%, at least about 90%, or at least about 95% identical to LLLSLILVSVGFVVTVFGVII (SEQ ID NO: 139). %, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to a chimeric inhibitory receptor, optionally wherein the transmembrane domain comprises the amino acid sequence of LLLSLILVSVGFVVTVFGVII (SEQ ID NO: 139), and the chimeric inhibitory receptor comprises a transmembrane domain derived from LIFR, and optionally wherein the transmembrane domain is VGLIIAILIPVAVAVIVGVVTSILC (SEQ ID NO: SEQ ID NO: 140), and optionally the transmembrane domain comprises the amino acid sequence of VGLIIAILIPVAVAVIVGVVTSILC (SEQ ID NO: 140), and the chimeric inhibitory receptor comprises a transmembrane domain derived from ERMAP, and optionallythe transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VALAVILPVLVLLIMVCLCLI (SEQ ID NO: 141), and optionally the transmembrane domain comprises the amino acid sequence of VALAVILPVLVLLIMVCLCLI (SEQ ID NO: 141), comprises a transmembrane domain derived from IL1RAPL2, and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to IELAGGLGAIFLLLVLLVVIY (SEQ ID NO: 142), ... VIY (SEQ ID NO: 142), wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from CDH5, and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to AVVAILLCILTITVITLLIFL (SEQ ID NO: 143), and optionally , the transmembrane domain comprises the amino acid sequence of AVVAILLCILTITVITLLIFL (SEQ ID NO: 143), and the chimeric inhibitory receptor comprises a transmembrane domain derived from MPZL1, and optionally the transmembrane domain has at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%,or about 100% identical, and optionally the transmembrane domain comprises the amino acid sequence of FPVWVVVGIVTAVVLGLTLLI (SEQ ID NO: 144), and the chimeric inhibitory receptor comprises a transmembrane domain derived from MPZ, and optionally the transmembrane domain is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, or at least about 98% identical to YGVVLGAVIGGVLGVVLLLLLLFYVV (SEQ ID NO: 145). and optionally the transmembrane domain comprises an amino acid sequence that is at least about 98%, at least about 99%, or about 100% identical to YGVVLGAVIGGVLGVVLLLLLLFYVV (SEQ ID NO: 145), and the chimeric inhibitory receptor comprises a transmembrane domain derived from FCGR2B, and optionally the transmembrane domain is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about and the chimeric inhibitory receptor comprises an amino acid sequence that is at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to a chimeric inhibitory receptor, optionally wherein the transmembrane domain comprises the amino acid sequence of SSSPMGIIVAVVTGIAVAAIVAA (SEQ ID NO: 146), and the chimeric inhibitory receptor comprises a transmembrane domain derived from SIGLEC-6, and optionally wherein the transmembrane domain is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94% identical to a chimeric inhibitory receptor, optionally wherein the transmembrane domain is at least about 80%, at least about 85%, at least about 90%, at least about 91 ... and the chimeric inhibitory receptor comprises an amino acid sequence that is at least about 2%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of LGAVWGASITTLVFLCVCFIF (SEQ ID NO: 147), and the chimeric inhibitory receptor comprises a transmembrane domain derived from MPIG6B, and optionally the transmembrane domain is at least about 80%, at least about 85%, at least about 96% identical to the amino acid sequence of LLIPLLGAGLVLGLGALGLVW (SEQ ID NO: 148). 5%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical, and optionally the transmembrane domain comprises the amino acid sequence of LLIPLLGAGLVLGLGALGLVW (SEQ ID NO: 148), and the chimeric inhibitory receptor comprises a transmembrane domain derived from VSIG4., and optionally the transmembrane domain is VFAIILIISLCCMVVFT MAYI (SEQ ID NO: 149), and optionally the transmembrane domain comprises the amino acid sequence of VFAIILIISLCCMVVFTMAYI (SEQ ID NO: 149), and the chimeric inhibitory receptor comprises a transmembrane domain derived from SIGLEC-12;Optionally, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to FGGAGATALVFLYFCIIFVVV (SEQ ID NO: 150), and optionally the transmembrane domain comprises the amino acid sequence of FGGAGATALVFLYFCIIFVVV (SEQ ID NO: 150), and The L1 inhibitory receptor comprises a transmembrane domain derived from LIR8, optionally wherein the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VVTGVSVAFVLLLFLLLFLLL (SEQ ID NO: 151), and optionally wherein the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VVTGVSVAFVLLLFLLLFLLL (SEQ ID NO: 151), LLLFLLL (SEQ ID NO: 151), and the chimeric inhibitory receptor comprises a transmembrane domain derived from IRTA1. Optionally, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VAAGATGGLLSALLLAVALLF (SEQ ID NO: 152). , optionally the transmembrane domain comprises the amino acid sequence of VAAGATGGLLSALLLAVALLF (SEQ ID NO: 152), and the chimeric inhibitory receptor comprises a transmembrane domain derived from KIR2DL4, and optionally the transmembrane domain has a sequence identical to at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%,and wherein the chimeric inhibitory receptor comprises an amino acid sequence that is at least about 99%, or about 100%, identical to LHILIGTSVAIILFIILFFFL (SEQ ID NO: 154), and optionally the transmembrane domain comprises the amino acid sequence of AVIRYSVAIILFTILPFFLLH (SEQ ID NO: 153), and the chimeric inhibitory receptor comprises a transmembrane domain derived from KIR2DL5, and optionally the transmembrane domain is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% identical to LHILIGTSVAIILFIILFFFL (SEQ ID NO: 154). and wherein the chimeric inhibitory receptor comprises an amino acid sequence that is at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of LHILIGTSVAIILFIILFFFL (SEQ ID NO: 154), and the chimeric inhibitory receptor comprises a transmembrane domain derived from SIGLEC-7, and optionally the transmembrane domain is at least about 80%, at least about 85%, at least about 90%, at least about 91% identical to GAVGGAGATALVFLSFCVIFIVV (SEQ ID NO: 155). %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of GAVGGAGATALVFLSFCVIFIVV (SEQ ID NO: 155), and the chimeric inhibitory receptor comprises a transmembrane domain derived from FCRH3, and optionally the transmembrane domain is at least and the chimeric inhibitory receptor comprises an amino acid sequence that is about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to any of the chimeric inhibitory receptors, and optionally the transmembrane domain comprises the amino acid sequence of AAGITGLVLSILVLAAAAALL (SEQ ID NO: 156), and the chimeric inhibitory receptor comprises a transmembrane domain derived from PCDHGC5, and optionally the transmembrane domain isand wherein the chimeric inhibitory receptor comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LIVALATVSLLSLVTFTFLSA (SEQ ID NO: 157), and optionally the transmembrane domain comprises the amino acid sequence of LIVALATVSLLSLVTFTFLSA (SEQ ID NO: 157), and the chimeric inhibitory receptor is derived from CDH11. and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to GALIAILACIVILLVIVVLFVTL (SEQ ID NO: 158). and the chimeric inhibitory receptor comprises an amino acid sequence of SEQ ID NO: 158), wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from IMPG2, and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VIIGITIASVVGLLVIFSAII (SEQ ID NO: 159), and optionally the transmembrane domain or the chimeric inhibitory receptor comprises a transmembrane domain derived from DSCAM, and optionally the transmembrane domain has at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 100%, at least about 101%, at least about 102%, at least about 103%, at least about 104%, at least about 105%, at least about 106%, at least about 107%, at least about 108%, at least about 109%, at least about 110%, at least about 111%, at least about 112%, at least about 113%, at least about 114%, at least about 115%, at least about 116%, at least about 117%, at least about 118%, at least about 119%, at least about 120%, at least about 121%, at least about 122%, at least about 123%, at least about 124%, at least about 125%, at least about 126%, at least about 127%, at least about 128%, at least about 129%, at least about 130%, at least about 131%, at least about 132%, at least about 133%, at least about 134%, at least about 135%, at least about 136%, at least about 137%, at least about 138%, at least about 139%, at least about 140%, at least about 141%, at least about 142%, at least about 143%, at least about 144%, at least about 145%, at least about 146%, at least about 147%, at least about 148%, at least aboutor an amino acid sequence that is about 100% identical, and optionally the transmembrane domain comprises the amino acid sequence of LVTISCILVGVLLLFVLLLVV (SEQ ID NO: 160).

[0012] In some embodiments, (i) the protein is not expressed on a target tumor, optionally the protein is expressed on a non-tumor cell, optionally the protein is expressed on a non-tumor cell derived from a tissue selected from the group consisting of brain, neuronal tissue, endocrine glands, endothelium, bone, bone marrow, immune system, muscle, lung, liver, gallbladder, pancreas, gastrointestinal tract, kidney, urinary bladder, male reproductive organs, female reproductive organs, adipose, soft tissue, and skin, and / or (ii) the extracellular protein binding domain is a ligand-binding domain, a receptor-binding domain, and / or an antigen-binding domain. and optionally the antigen-binding domain comprises an antibody, an antigen-binding fragment of an antibody, a F(ab) fragment, a F(ab') fragment, a single-chain variable fragment (scFv), or a single-domain antibody (sdAb), and optionally the antigen-binding domain comprises a single-chain variable fragment (scFv), and optionally the scFv comprises a heavy chain variable domain (VH) and a light chain variable domain (VL), and optionally the VH and VL are separated by a peptide linker, and optionally the peptide linker is selected from the group consisting of GGS (SEQ ID NO: 47), GGSGGS (SEQ ID NO: 48), GGSGGS GGS (SEQ ID NO: 49), GGSGGSGGSGGS (SEQ ID NO: 50), GGSGGSGGGSGGSGGS (SEQ ID NO: 51), GGGS (SEQ ID NO: 52), GGGSGGGS (SEQ ID NO: 53), GGGSGGGSGGGS (SEQ ID NO: 54), GGGSGGGSGGGSGGGS (SEQ ID NO: 55), GGGSGGGSGGGSGGGSGGGS (SEQ ID NO: 56), GGGGS (SEQ ID NO: 57), GGGGSGGGGS (SEQ ID NO: 58), GGGGSGGGGSGGGGS (SEQ ID NO: 59), GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 60 ), GGGGSGGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 61), GGGGSGGGGSGGGGSQSV (SEQ ID NO: 63), GSTSGSGKPGSGEGSTKG (SEQ ID NO: 64), SGGGGSGGGGSGGGGSGGGGSGGGSLQ (SEQ ID NO: 65), and TTTPAPRPPTPAPTIALQPLSLRPEACRPAAGGAVHTRGLDFACDQTTPGERSSLPAFYPGTSGSCSGCGSLSLP (SEQ ID NO: 62); and optionally the scFv comprises an amino acid sequence selected from the group consisting of:The structure includes VH-L-VL or VL-L-VH, where VH is a heavy chain variable domain, L is a peptide linker, and VL is a light chain variable domain.

[0013] In some embodiments, the chimeric inhibitory receptor further comprises a spacer region disposed between the extracellular protein binding domain and the transmembrane domain and operably linked, e.g., physically linked, to each of the extracellular protein binding domain and the transmembrane domain, optionally wherein the spacer region is derived from a protein selected from the group consisting of CD8α, CD4, CD7, CD28, IgG1, IgG4, FcγRIIIα, LNGFR, and PDGFR, optionally wherein the spacer region is (SEQ ID NO: 67), ESKYGPPCPSCP (SEQ ID NO: 68), ESKYGPPAPSAP (SEQ ID NO: 69), ESKYGPPCPPCP (SEQ ID NO: 70), EPKSCDKTHTCP (SEQ ID NO: 71), AAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRN (SEQ ID NO: 72), ACPTGLYTHSGECCKACNLGEGVAQPCGANQTVCEPCLDSVTFSDVVSATEPCKPCTECVGLQSMSAPCVEADDAVCRCAYGYYQDETTGRCEACRVCEAGSGLVFSCQDKQNTVCEECPDGTYSDEADAEC (SEQ ID NO: 74), ACPTGLYTHSGECCKACNLGEGVAQPCGANQTVC (SEQ ID NO: 75), AVGQDTQEVIVVPHSLPFKV (SEQ ID NO: 76),ESKYGPPCPSCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 183), and ESKYGPPCPSCPGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 184).

[0014] In some embodiments, the chimeric inhibitory receptor further comprises an intracellular spacer region disposed between the transmembrane domain and one of the one or more intracellular signaling domains and operably linked, e.g., physically linked, to each of the transmembrane domain and one of the one or more intracellular signaling domains. In some embodiments, the inhibitory chimeric receptor further comprises an enzyme inhibitory domain, optionally capable of preventing, attenuating, or inhibiting activation of the tumor-targeting chimeric receptor when expressed on an immunomodulatory cell compared to an otherwise identical chimeric inhibitory receptor lacking the enzyme inhibitory domain, and optionally, the enzyme inhibitory domain comprises an enzyme catalytic domain, optionally derived from an enzyme selected from the group consisting of CSK, SHP-1, PTEN, CD45, CD148, PTP-MEG1, PTP-PEST, c-CBL, CBL-b, PTPN22, LAR, PTPH1, SHIP-1, and RasGAP.

[0015] In some embodiments, the tumor-targeting chimeric receptor is a chimeric antigen receptor (CAR) or an engineered T cell receptor (TCR). In some embodiments, the immunoregulatory cell is selected from the group consisting of T cells, CD8+ T cells, CD4+ T cells, gamma-delta T cells, cytotoxic T lymphocytes (CTLs), regulatory T cells, virus-specific T cells, natural killer T (NKT) cells, natural killer (NK) cells, B cells, tumor-infiltrating lymphocytes (TILs), innate lymphocytes, mast cells, eosinophils, basophils, neutrophils, myeloid cells, macrophages, monocytes, dendritic cells, ESC-derived cells, and iPSC-derived cells, and optionally, the immunoregulatory cell is a natural killer (NK) cell.

[0016] Another embodiment of the present disclosure provides a composition comprising a chimeric inhibitory receptor of the present disclosure and a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, or a combination thereof.

[0017] Another embodiment of the present disclosure provides an engineered nucleic acid encoding a chimeric inhibitory receptor of the present disclosure.

[0018] Another embodiment of the present disclosure provides an expression vector comprising an engineered nucleic acid of the present disclosure.

[0019] Another embodiment of the present disclosure provides a composition comprising an engineered nucleic acid or expression vector of the present disclosure and a pharmaceutically acceptable carrier.

[0020] Another embodiment of the present disclosure provides a production cell or isolated immunomodulatory cell comprising a chimeric inhibitory receptor, engineered nucleic acid, or expression vector of the present disclosure.

[0021] Another embodiment of the present disclosure provides a composition comprising an isolated cell of the present disclosure and a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, or a combination thereof.

[0022] Another embodiment of the present disclosure also provides a method of preventing, attenuating, or inhibiting a cell-mediated immune response induced by a tumor-targeting chimeric receptor expressed on the surface of an immunomodulatory cell, comprising engineering an immunomodulatory cell to express a chimeric inhibitory receptor of the present disclosure on its surface, wherein upon binding of a cognate antigen to the chimeric inhibitory receptor, the intracellular signaling domain prevents, attenuates, or inhibits activation of the tumor-targeting chimeric receptor.

[0023] Another embodiment of the present disclosure provides a method for preventing, attenuating, or inhibiting activation of a tumor-targeting chimeric receptor expressed on the surface of an immunomodulatory cell, comprising contacting an isolated cell or composition of the present disclosure with a cognate antigen of the chimeric inhibitory receptor under conditions suitable for the chimeric inhibitory receptor to bind the cognate antigen, wherein upon binding of the antigen to the chimeric inhibitory receptor, the intracellular signaling domain prevents, attenuates, or inhibits activation of the tumor-targeting chimeric receptor.

[0024] Another embodiment of the present disclosure relates to a method for producing a polypeptide comprising: (1) an extracellular protein binding domain; (2) a transmembrane domain, wherein the transmembrane domain is operably linked to the extracellular protein binding domain; and (3) one or more intracellular signaling domains, wherein the one or more intracellular signaling domains are operably linked to the transmembrane domain, wherein the one or more intracellular signaling domains are each selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAP, IL2RAP ... and a chimeric inhibitory receptor comprising: a chimeric inhibitory receptor derived from a protein selected from the group consisting of 1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM, wherein at least one of the one or more intracellular signaling domains is capable of preventing, attenuating, or inhibiting activation of the tumor-targeting chimeric receptor expressed on an immunomodulatory cell.

[0025] In some embodiments, the transmembrane domain is derived from the same protein as one of the one or more intracellular signaling domains. In some embodiments, the transmembrane domain further comprises at least a portion of the extracellular domain of the same protein. In some embodiments, the transmembrane domain is derived from a first protein and the one or more intracellular signaling domains are derived from a different protein than the first protein. In some embodiments, the one or more intracellular signaling domains are two intracellular signaling domains.

[0026] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from PECAM-1 and a second intracellular signaling domain derived from a protein selected from the group consisting of CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0027] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from CD72 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0028] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from IRTA2 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0029] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from IRTA4 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0030] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from an NKIR and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0031] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from IL1RAP and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, PTPRO, PTPRZ1, TLT1, SLAMF1 and SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0032] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from PTPRO and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0033] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from PTPRZ1 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0034] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from TLT1 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0035] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from SLAMF1 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0036] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from SLAMF5 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0037] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from PCDHGC3 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0038] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from LIFR and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0039] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from ERMAP and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0040] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from IL1RAPL2 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0041] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from CDH5 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0042] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from MPZL1 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0043] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from MPZ and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0044] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from FCGR2B and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0045] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from SIGLEC-6 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0046] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from MPIG6B and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0047] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from VSIG4 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0048] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from SIGLEC-12 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0049] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from LIR8 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0050] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from IRTA1 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0051] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from KIR2DL4 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0052] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from KIR2DL5 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0053] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from SIGLEC-7 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0054] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from FCRH3 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0055] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from PCDHGC5 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, CDH11, IMPG2, and DSCAM.

[0056] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from CDH11 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, IMPG2, and DSCAM.

[0057] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from IMPG2 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, CDH11, and DSCAM.

[0058] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from DSCAM and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, CDH11, and IMPG2.

[0059] In some embodiments, one of the one or more intracellular signaling domains is derived from PECAM- 1. In some embodiments, the intracellular signaling domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to KCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEANSHYGHNDDVRNHAMKPINDNKEPLNSDVQYTEVQVSSAESHKDLGKKDTETVYSEVRKAVPDAVESRYSRTEGSLDGT (SEQ ID NO: 1). In some embodiments, the intracellular signaling domain comprises the amino acid sequence of KCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEANSHYGHNDDVRNHAMKPINDNKEPLNSDVQYTEVQVSSAESHKDLGKKDTETVYSEVRKAVPDAVESRYSRTEGSLDGT (SEQ ID NO: 1).

[0060] In some embodiments, one of the one or more intracellular signaling domains is derived from CD72. In some embodiments, the intracellular signaling domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to MAEAITYADLRFVKAPLKKSISSRLGQDPGADDDGEITYENVQVPAVLGVPSSLASSVLGDKAAVKSEQPTASWRAVTSPAVGRILPCRTTCLRY (SEQ ID NO: 2). In some embodiments, the intracellular signaling domain comprises the amino acid sequence of MAEAITYADLRFVKAPLKKSISSRLGQDPGADDDGEITYENVQVPAVLGVPSSLASSVLGDKAAVKSEQPTASWRAVTSPAVGRILPCRTTCLRY (SEQ ID NO: 2).

[0061] In some embodiments, one of the one or more intracellular signaling domains is derived from IRTA2. In some embodiments, the intracellular signaling domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LSRKAGRKPASDPARSPSDSDSQEPTYHNVPAWEELQPVYTNANPRGENVVYSEVRIIQEKKKHAVASDPRHLRNKGSPIIYSEVKVASTPVSGSLFLASSAPHR (SEQ ID NO: 3). In some embodiments, the intracellular signaling domain comprises the amino acid sequence of LSRKAGRKPASDPARSPSDSDSQEPTYHNVPAWEELQPVYTNANPRGENVVYSEVRIIQEKKKHAVASDPRHLRNKGSPIIYSEVKVASTPVSGSLFLASSAPHR (SEQ ID NO: 3).

[0062] In some embodiments, one of the one or more intracellular signaling domains is derived from IRTA4. In some embodiments, the intracellular signaling domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to HKISGESSATNEPRGASRPNPQEFTYSSPTPDMEELQPVYVNVGSVDVDVVYSQVWSMQQPESSANIRTLLENKDSQVIYSSVKKS (SEQ ID NO: 4). In some embodiments, the intracellular signaling domain comprises the amino acid sequence of HKISGESSATNEPRGASRPNPQEFTYSSPTPDMEELQPVYVNVGSVDVDVVYSQVWSMQQPESSANIRTLLENKDSQVIYSSVKKS (SEQ ID NO: 4).

[0063] In some embodiments, one of the one or more intracellular signaling domains is derived from NKIR. In some embodiments, the intracellular signaling domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to WRMMKYQQKAAGMSPEQVLQPLEGDLCYADLTLQLAGTSPQKATTKLSSAQVDQVEVEYVTMASLPKEDISYASLTLGAEDQEPTYCNMGHLSSHLPGRGPEEPTEYSTISRP (SEQ ID NO: 5). In some embodiments, the intracellular signaling domain comprises the amino acid sequence of WRMMKYQQKAAGMSPEQVLQPLEGDLCYADLTLQLAGTSPQKATTKLSSAQVDQVEVEYVTMASLPKEDISYASLTLGAEDQEPTYCNMGHLSSHLPGRGPEEPTEYSTISRP (SEQ ID NO: 5).

[0064] In some embodiments, one of the one or more intracellular signaling domains is derived from IL1RAP. In some embodiments, the intracellular signaling domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to YRAHFGTDETILDGKEYDIYVSYARNAEEEEFVLLTLRGVLENEFGYKLCIFDRDSLPGGIVTDETLSFIQKSRRLLVVLSPNYVLQGTQALLELKAGLENMASRGNINVILVQYKAVKETKVKELKRAKTVLTVIKWKGEKSKYPQGRFWKQLQVAMPVKKSPRRSSSDEQGLSYSSLKNV (SEQ ID NO: 6). In some embodiments, the intracellular signaling domain comprises the amino acid sequence of YRAHFGTDETILDGKEYDIYVSYARNAEEEEFVLLTLRGVLENEFGYKLCIFDRDSLPGGIVTDETLSFIQKSRRLLVVLSPNYVLQGTQALLELKAGLENMASRGNINVILVQYKAVKETKVKELKRAKTVLTVIKWKGEKSKYPQGRFWKQLQVAMPVKKSPRRSSSDEQGLSYSSLKNV (SEQ ID NO: 6).

[0065] In some embodiments, one of the one or more intracellular signaling domains is derived from PTPRO. In some embodiments, the intracellular signaling domain is LRKKHLQMARECGAGTFVNFASLERDGKLPYNWRRSIFAFLTLLPSCLWTDYLLAFYINPWSKNGLKKRKLTNPVQLDDFDAYIKDMAKDSDYKFSLQFEELKLIGLDIPHFAADLPLNRCKNRYTNILPYDFSRVRLVSMNEEEGADYINANYIPGYNSPQEYIATQGPLPETRNDFWKMVLQQKSQIIVMLTQCNEKRRVKCDHYWPFTEEPIAYGDITVEMISEEEQDDWACRHFRINYADEMQD It comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VMHFNYTAWPDHGVPTANAAESILQFVHMVRQQATKSKGPMIIHCSAGVGRTGTFIALDRLLQHIRDHEFVDILGLVSEMRSYRMSMVQTEEQYIFIHQCVQLMWMKKKQQFCISDVIYENVSKS (SEQ ID NO: 7).In some embodiments, the intracellular signaling domain comprises the amino acid sequence of LRKKHLQMARECGAGTFVNFASLERDGKLPYNWRRSIFAFLTLLPSCLWTDYLLAFYINPWSKNGLKKRKLTNPVQLDDFDAYIKDMAKDSDYKFSLQFEELKLIGLDIPHFAADLPLNRCKNRYTNILPYDFSRVRLVSMNEEEGADYINANYIPGYNSPQEYIATQGPLPETRNDFWKMVLQQKSQIIVMLTQCNEKRRVKCDHYWPFTEEPIAYGDITVEMISEEEQDDWACRHFRINYADEMQDVMHFNYTAWPDHGVPTANAAESILQFVHMVRQQATKSKGPMIIHCSAGVGRTGTFIALDRLLQHIRDHEFVDILGLVSEMRSYRMSMVQTEEQYIFIHQCVQLMWMKKKQQFCISDVIYENVSKS (SEQ ID NO: 7).

[0066] In some embodiments, one of the one or more intracellular signaling domains is derived from PTPRZ1. In some embodiments, the intracellular signaling domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to (SEQ ID NO:8).In some embodiments, the intracellular signaling domain comprises the amino acid sequence of (SEQ ID NO: 8).

[0067] In some embodiments, one of the one or more intracellular signaling domains is derived from TLT1. In some embodiments, the intracellular signaling domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to MAKRKQGNRLGVCGRFLSSRVSGMNPSSVVHHVSDSGPAAELPLDVPHIRLDSPPSFDNTTYTSLPLDSPSGKPSLPAPSSLPPLPPKVLVCSKPVTYATVIFPGGNKGGGTSCGPAQNPPNNQTPSS (SEQ ID NO: 9). In some embodiments, the intracellular signaling domain comprises the amino acid sequence of MAKRKQGNRLGVCGRFLSSRVSGMNPSSVVHHVSDSGPAAELPLDVPHIRLDSPPSFDNTTYTSLPLDSPSGKPSLPAPSSLPPLPPKVLVCSKPVTYATVIFPGGNKGGGTSCGPAQNPPNNQTPSS (SEQ ID NO: 9).

[0068] In some embodiments, one of the one or more intracellular signaling domains is derived from SLAMF1. In some embodiments, the intracellular signaling domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to QLRRRGKTNHYQTTVEKKSLTIYAQVQKPGPLQKKLDSFPAQDPCTTIYVAATEPVPESVQETNSITVYASVTLPES (SEQ ID NO: 10). In some embodiments, the intracellular signaling domain comprises the amino acid sequence of QLRRRGKTNHYQTTVEKKSLTIYAQVQKPGPLQKKLDSFPAQDPCTTIYVAATEPVPESVQETNSITVYASVTLPES (SEQ ID NO: 10).

[0069] In some embodiments, one of the one or more intracellular signaling domains is derived from SLAMF5. In some embodiments, the intracellular signaling domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to RLFKRRQGRIFPEGSCLNTFTKNPYAASKKTIYTYIMASRNTQPAESRIYDEILQSKVLPSKEEPVNTVYSEVQFADKMGKASTQDSKPPGTSSYEIVI (SEQ ID NO: 11). In some embodiments, the intracellular signaling domain comprises the amino acid sequence of RLFKRRQGRIFPEGSCLNTFTKNPYAASKKTIYTYIMASRNTQPAESRIYDEILQSKVLPSKEEPVNTVYSEVQFADKMGKASTQDSKPPGTSSYEIVI (SEQ ID NO: 11).

[0070] In some embodiments, one of the one or more intracellular signaling domains is derived from PCDHGC3. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to FKVYKWKQSRDLYRAPVSSLYRTPGPSLHADAVRGGLMSPHLYHQVYLTTDSRRSDPLLKKPGAASPLASRQNTLRSCDPVFYRQVLGAESAPPGQQAPPNTDWRFSQAQRPGTSGSQNGDDTGTWPNNQFDTEMLQAMILASASEAADGSSTLGGGAGTMGLSARYGPQFTLQHVPDYRQNVYIPGSNATLTNAAGKRDGKAPAGGNGNKKKSGKKEKK (SEQ ID NO: 95). In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of FKVYKWKQSRDLYRAPVSSLYRTPGPSLHADAVRGGLMSPHLYHQVYLTTDSRRSDPLLKKPGAASPLASRQNTLRSCDPVFYRQVLGAESAPPGQQAPPNTDWRFSQAQRPGTSGSQNGDDTGTWPNNQFDTEMLQAMILASASEAADGSSTLGGGAGTMGLSARYGPQFTLQHVPDYRQNVYIPGSNATLTNAAGKRDGKAPAGGNGNKKKSGKKEKK (SEQ ID NO: 95).

[0071] In some embodiments, one of the one or more intracellular signaling domains is derived from LIFR. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to YRKREWIKETFYPDIPNPENCKALQFQKSVCEGSSALKTLEMNPCTPNNVEVLETRSAFPKIEDTEIISPVAERPEDRSDAEPENHVVVSYCPPIIEEEIPNPAADEAGGTAQVIYIDVQSMYQPQAKPEEEQENDPVGGAGYKPQMHLPINSTVEDIAAEEDLDKTAGYRPQANVNTWNLVSPDSPRSIDSNSEIVSFGSPCSINSRQFLIPPKDEDSPKSNGGGWSFTNFFQNKPND (SEQ ID NO: 96). In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of YRKREWIKETFYPDIPNPENCKALQFQKSVCEGSSALKTLEMNPCTPNNVEVLETRSAFPKIEDTEIISPVAERPEDRSDAEPENHVVVSYCPPIIEEEIPNPAADEAGGTAQVIYIDVQSMYQPQAKPEEEQENDPVGGAGYKPQMHLPINSTVEDIAAEEDLDKTAGYRPQANVNTWNLVSPDSPRSIDSNSEIVSFGSPCSINSRQFLIPPKDEDSPKSNGGGWSFTNFFQNKPND (SEQ ID NO: 96).

[0072] In some embodiments, one of the one or more intracellular signaling domains is derived from ERMAP. In some embodiments, one of the one or more intracellular signaling domains is WKQRRAKEKLLYEHVTEVDNLLSDHAKEKGKLHKAVKKLRSELKLKRAAANSGWRRARLHFVAVTLDPDTAHPKLILSEDQRCVRLGDRRQPVPDNPQRFDFVVSILGSEYFTTGCHYWEVYVGDKTKWILGVCSESVSRKGKVTASPANGHWLLRQSRGNEYEALTSPQTSFRLKEPPRCVGIFLDYEAGVISFYNVTNKSHIFT FTHNFSGPLRPFFEPCLHDGGKNTAPLVICSELHKSEESIVPRPEGKGHANGDVSLKVNSSLLPPK comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to ape LKDIILSLPPDLGPALQELKAPSF (SEQ ID NO: 97). In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of WKQRRAKEKLLYEHVTEVDNLLSDHAKEKGKLHKAVKKLRSELKLKRAAANSGWRRARLHFVAVTLDPDTAHPKLILSEDQRCVRLGDRRQPVPDNPQRFDFVVSILGSEYFTTGCHYWEVYVGDKTKWILGVCSESVSRKGKVTASPANGHWLLRQSRGNEYEALTSPQTSFRLKEPPRCVGIFLDYEAGVISFYNVTNKSHIFTFTHNFSGPLRPFFEPCLHDGGKNTAPLVICSELHKSEESIVPRPEGKGHANGDVSLKVNSSLLPPKAPELKDIILSLPPDLGPALQELKAPSF (SEQ ID NO: 97).

[0073] In some embodiments, one of the one or more intracellular signaling domains is derived from IL1RAPL2. In some embodiments, one of the one or more intracellular signaling domains is KCYNIELMLFYRQHFGADETNDDNKEYDAYLSYTKVDQDTLDCDNPEEEQFALEVLPDVLEKHYGYKLFIPERDLIPSGTYMEDLTRYVEQSRRLIIVLTPDYILRRGWSIFELESRLHNMLVSGEIKVILIECTELKGKVNCQEVESLKRSIKLLSLIKWKGSKSSKLNSKFWKHLVYEMPIKKKEMLPRCHVLDSAEQGLFGELQPIPSI It comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to AMTSTSATLVSSQADLPEFHPSDSMQIRHCCRGYKHEIPATTLPVPSLGNHHTYCNLPLTLLNGQLPLNNTLKDTQEFHRNSSLLPLSSKELSFTSDIW (SEQ ID NO: 98). In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of KCYNIELMLFYRQHFGADETNDDNKEYDAYLSYTKVDQDTLDCDNPEEEQFALEVLPDVLEKHYGYKLFIPERDLIPSGTYMEDLTRYVEQSRRLIIVLTPDYILRRGWSIFELESRLHNMLVSGEIKVILIECTELKGKVNCQEVESLKRSIKLLSLIKWKGSKSSKLNSKFWKHLVYEMPIKKKEMLPRCHVLDSAEQGLFGELQPIPSIAMTSTSATLVSSQADLPEFHPSDSMQIRHCCRGYKHEIPATTLPVPSLGNHHTYCNLPLTLLNGQLPLNNTLKDTQEFHRNSSLLPLSSKELSFTSDIW (SEQ ID NO: 98).

[0074] In some embodiments, one of the one or more intracellular signaling domains is derived from CDH5. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to RRRLRKQARAHGKSVPEIHEQLVTYDEEGGGEMDTTSYDVSVLNSVRRGGAKPPRPALDARPSLYAQVQKPPRHAPGAHGGPGEMAAMIEVKKDEADHDGDGPPYDTLHIYGYEGSESIAESLSSLGTDSSDSDVDYDFLNDWGPRFKMLAELYGSDPREELLY (SEQ ID NO:99). In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of RRRLRKQARAHGKSVPEIHEQLVTYDEEGGGEMDTTSYDVSVLNSVRRGGAKPPRPALDARPSLYAQVQKPPRHAPGAHGGPGEMAAMIEVKKDEADHDGDGPPYDTLHIYGYEGSESIAESLSSLGTDSSDSDVDYDFLNDWGPRFKMLAELYGSDPREELLY (SEQ ID NO: 99).

[0075] In some embodiments, one of the one or more intracellular signaling domains is derived from MPZL1. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SMILAVLYRRKNSKRDYTGCSTSESLSPVKQAPRKSPSDTEGLVKSLPSGSHQGPVIYAQLDHSGGHHSDKINKSESVVYADIRKN (SEQ ID NO: 100). In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of SMILAVLYRRKNSKRDYTGCSTSESLSPVKQAPRKSPSDTEGLVKSLPSGSHQGPVIYAQLDHSGGHHSDKINKSESVVYADIRKN (SEQ ID NO: 100).

[0076] In some embodiments, one of the one or more intracellular signaling domains is derived from MPZ. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to RYCWLRRQAALQRRLSAMEKGKLHKPGKDASKRGRQTPVLYAMLDHSRSTKAVSEKKAKGLGESRKDKK (SEQ ID NO: 101). In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of RYCWLRRQAALQRRLSAMEKGKLHKPGKDASKRGRQTPVLYAMLDHSRSTKAVSEKKAKGLGESRKDKK (SEQ ID NO: 101).

[0077] In some embodiments, one of the one or more intracellular signaling domains is derived from FCGR2B. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VVALIYCRKKRISALPGYPECREMGETLPEKPANPTNPDEADKVGAENTITYSLLMHPDALEEPDDQNRI (SEQ ID NO: 102). In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of VVALIYCRKKRISALPGYPECREMGETLPEKPANPTNPDEADKVGAENTITYSLLMHPDALEEPDDQNRI (SEQ ID NO: 102).

[0078] In some embodiments, one of the one or more intracellular signaling domains is derived from SIGLEC-6. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to RVKTRRKKAAQPVQNTDDVNPVMVSGSRGHQHQFQTGIVSDHPAEAGPISEDEQELHYAVLHFHKVQPQEPKVTDTEYSEIKIHK (SEQ ID NO: 103). In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence RVKTRRKKAAQPVQNTDDVNPVMVSGSRGHQHQFQTGIVSDHPAEAGPISEDEQELHYAVLHFHKVQPQEPKVTDTEYSEIKIHK (SEQ ID NO: 103).

[0079] In some embodiments, one of the one or more intracellular signaling domains is derived from MPIG6B. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to WLHRRLPPQPIRPLPRFAPLVKTEPQRPVKEEEPKIPGDLDQEPSLLYADLDHLALSRPRRLSTADPADASTIYAVVV (SEQ ID NO: 104). In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of WLHRRLPPQPIRPLPRFAPLVKTEPQRPVKEEEPKIPGDLDQEPSLLYADLDHLALSRPRRLSTADPADASTIYAVVV (SEQ ID NO: 104).

[0080] In some embodiments, one of the one or more intracellular signaling domains is derived from VSIG4. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to MLCRKTSQQEHVYEAARAHAREANDSGETMRVAIFASGCSSDEPTSQNLGNNYSDEPCIGQEYQIIAQINGNYARLLDTVPLDYEFLATEGKSVC (SEQ ID NO: 105). In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of MLCRKTSQQEHVYEAARAHAREANDSGETMRVAIFASGCSSDEPTSQNLGNNYSDEPCIGQEYQIIAQINGNYARLLDTVPLDYEFLATEGKSVC (SEQ ID NO: 105).

[0081] In some embodiments, one of the one or more intracellular signaling domains is derived from SIGLEC- 12. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to RSCRKKSARPAVGVGDTGMEDANAVRGSASQGPLIESPADDSPPHHAPPALATPSPEEGEIQYASLSFHKARPQYPQEQEAIGYEYSEINIPK (SEQ ID NO: 106). In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of RSCRKKSARPAVGVGDTGMEDANAVRGSASQGPLIESPADDSPPHHAPPALATPSPEEGEIQYASLSFHKARPQYPQEQEAIGYEYSEINIPK (SEQ ID NO: 106).

[0082] In some embodiments, one of the one or more intracellular signaling domains is derived from LIR8. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to RHRHQSKHRTSAHFYRPAGAAGPEPKDQGLQKRASPVADIQEEILNAAVKDTQPKDGVEMDAPAAASEAPQDVTYAQLHSLTLRREATEPPPSQEREPPAEPSIYAPLAIH (SEQ ID NO: 107). In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence RHRHQSKHRTSAHFYRPAGAAGPEPKDQGLQKRASPVADIQEEILNAAVKDTQPKDGVEMDAPAAASEAPQDVTYAQLHSLTLRREATEPPPSQEREPPAEPSIYAPLAIH (SEQ ID NO: 107).

[0083] In some embodiments, one of the one or more intracellular signaling domains is derived from IRTA1. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to HCWRRRKSGVGFLGDETRLPPAPGPGESSHSICPAQVELQSLYVDVHPKKGDLVYSEIQTTQLGEEEEANTSRTLLEDKDVSVVYSEVKTQHPDNSAGKISSKDEES (SEQ ID NO: 108). In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of HCWRRRKSGVGFLGDETRLPPAPGPGESSHSICPAQVELQSLYVDVHPKKGDLVYSEIQTTQLGEEEEANTSRTLLEDKDVSVVYSEVKTQHPDNSAGKISSKDEES (SEQ ID NO: 108).

[0084] In some embodiments, one of the one or more intracellular signaling domains is derived from KIR2DL4. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to RWCSKKKDAAVMNQEPAGHRTVNREDSDEQDPQEVTYAQLDHCIFTQRKITGPSQRSKRPSTDTSVCIELPNAEPRALSPAHEHHSQALMGSSRETTALSQTQLASSNVPAAGI (SEQ ID NO: 109). In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of RWCSKKKDAAVMNQEPAGHRTVNREDSDEQDPQEVTYAQLDHCIFTQRKITGPSQRSKRPSTDTSVCIELPNAEPRALSPAHEHHSQALMGSSRETTALSQTQLASSNVPAAGI (SEQ ID NO: 109).

[0085] In some embodiments, one of the one or more intracellular signaling domains is derived from KIR2DL5. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LHCCCSNKKNAAVMDQEPAGDRTVNREDSDDQDPQEVTYAQLDHCVFTQTKITSPSQRPKTPPTDTTMYMELPNAKPRSLSPAHKHHSQALRGSSRETTALSQNRVASSHVPAAGI (SEQ ID NO: 110). In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of LHCCCSNKKNAAVMDQEPAGDRTVNREDSDDQDPQEVTYAQLDHCVFTQTKITSPSQRPKTPPTDTTMYMELPNAKPRSLSPAHKHHSQALRGSSRETTALSQNRVASSHVPAAGI (SEQ ID NO: 110).

[0086] In some embodiments, one of the one or more intracellular signaling domains is derived from SIGLEC-7. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to RSCRKKSARPAADVGDIGMKDANTIRGSASQGNLTESWADDNPRHHGLAAHSSGEEREIQYAPLSFHKGEPQDLSGQEATNNEYSEIKIPK (SEQ ID NO: 111). In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence RSCRKKSARPAADVGDIGMKDANTIRGSASQGNLTESWADDNPRHHGLAAHSSGEEREIQYAPLSFHKGEPQDLSGQEATNNEYSEIKIPK (SEQ ID NO: 111).

[0087] In some embodiments, one of the one or more intracellular signaling domains is derived from FCRH3. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to HYARARRKPGGLSATGTSSHSPSECQEPSSSRPSRIDPQEPTHSKPLAPMELEPMYSNVNPGDSNPIYSQIWSIQHTKENSANCPMMHQEHEELTVLYSELKKTHPDDSAGEASSRGRAHEEDDEENYENVPRVLLASDH (SEQ ID NO: 112). In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence HYARARRKPGGLSATGTSSHSPSECQEPSSSRPSRIDPQEPTHSKPLAPMELEPMYSNVNPGDSNPIYSQIWSIQHTKENSANCPMMHQEHEELTVLYSELKKTHPDDSAGEASSRGRAHEEDDEENYENVPRVLLASDH (SEQ ID NO: 112).

[0088] In some embodiments, one of the one or more intracellular signaling domains is derived from PCDHGC5. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to KCLQGNADGDGGGGQCCRRQDSPSPDFYKQSSPNLQVSSDGTLKYMEVTLRPTDSQSHCYRTCFSPASDGSDFTFLRPLSVQQPTALALEPDAIRSRSNTLRERSQQAPPNTDWRFSQAQRPGTSGSQNGDDTGTWPNNQFDTEMLQAMILASASEAADGSSTLGGGAGTMGLSARYGPQFTLQHVPDYRQNVYIPGSNATLTNAAGKRDGKAPAGGNGNKKKSGKKEKK (SEQ ID NO: 113). In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of KCLQGNADGDGGGGQCCRRQDSPSPDFYKQSSPNLQVSSDGTLKYMEVTLRPTDSQSHCYRTCFSPASDGSDFTFLRPLSVQQPTALALEPDAIRSRSNTLRERSQQAPPNTDWRFSQAQRPGTSGSQNGDDTGTWPNNQFDTEMLQAMILASASEAADGSSTLGGGAGTMGLSARYGPQFTLQHVPDYRQNVYIPGSNATLTNAAGKRDGKAPAGGNGNKKKSGKKEKK (SEQ ID NO: 113).

[0089] In some embodiments, one of the one or more intracellular signaling domains is derived from CDH11. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to RRQKKEPLIVFEEEDVRENIITYDDEGGGEEDTEAFDIATLQNPDGINGFIPRKDIKPEYQYMPRPGLRPAPNSVDVDDFINTRIQEADNDPTAPPYDSIQIYGYEGRGSVAGSLSSLESATTDSDLDYDYLQNWGPRFKKLADLYGSKDTFDDDS (SEQ ID NO: 114). In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of RRQKKEPLIVFEEEDVRENIITYDDEGGGEEDTEAFDIATLQNPDGINGFIPRKDIKPEYQYMPRPGLRPAPNSVDVDDFINTRIQEADNDPTAPPYDSIQIYGYEGRGSVAGSLSSLESATTDSDLDYDYLQNWGPRFKKLADLYGSKDTFDDDS (SEQ ID NO: 114).

[0090] In some embodiments, one of the one or more intracellular signaling domains is derived from IMPG2. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to YFFIRTLQAHHDRSERESPFSGSSRQPDSLSSIENAVKYNPVYESHRAGCEKYEGPYPQHPFYSSASGDVIGGLSREEIRQMYESSELSREEIQERMRVLELYANDPEFAAFVREQQVEEV (SEQ ID NO: 115). In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of YFFIRTLQAHHDRSERESPFSGSSRQPDSLSSIENAVKYNPVYESHRAGCEKYEGPYPQHPFYSSASGDVIGGLSREEIRQMYESSELSREEIQERMRVLELYANDPEFAAFVREQQVEEV (SEQ ID NO: 115).

[0091] In some embodiments, one of the one or more intracellular signaling domains is derived from DSCAM. In some embodiments, one of the one or more intracellular signaling domains is derived from DSCAM. In some embodiments, one of the one or more intracellular signaling domains is derived from DSCAM. It comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to TASPPKPQDGGRVMNMAVPKAHRPGDLIHLPPYLRMDFLLNRGGPGTSRDLSLGQACLEPQKSRTLKRPTVLEPIPMEAASSASSTREGQSWQPGAVATLPQREGAELGQAAKMSSSQESLLDSRGHLKGNNPYAKSYTLV (SEQ ID NO: 116).In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of RRRREQRLKRLRDAKSLAEMLMSKNTRTSDTLSKQQQTLRMHIDIPRAQLLIEERDTMETIDDRSTVLLTDADFGEAAKQKSLTVTHTVHYQSVSQATGPLVDVSDARPGTNPTTRRNAKAGPTARNRYASQWTLNRPHPTISAHTLTTDWRLPTPRAAGSVDKESDSYSVSPSQDTDRARSSMVSTESASSTYEELARAYEHAKMEEQLRHAKFTITECFISDTSSEQLTAGTNEYTDSLTSSTPSESGICRFTASPPKPQDGGRVMNMAVPKAHRPGDLIHLPPYLRMDFLLNRGGPGTSRDLSLGQACLEPQKSRTLKRPTVLEPIPMEAASSASSTREGQSWQPGAVATLPQREGAELGQAAKMSSSQESLLDSRGHLKGNNPYAKSYTLV (SEQ ID NO: 116).

[0092] In another embodiment, the present disclosure provides a chimeric inhibitory receptor comprising: (1) an extracellular protein binding domain; (2) a transmembrane domain, the transmembrane domain operably linked to the extracellular protein binding domain; and (3) one or more intracellular signaling domains, the one or more intracellular signaling domains operably linked to the transmembrane domain, wherein at least one of the one or more intracellular signaling domains comprises at least one immunoreceptor tyrosine-dependent switch motif (ITSM), or at least one ITIM and at least one phosphatase, and wherein at least one of the one or more intracellular signaling domains is capable of preventing, attenuating, or inhibiting activation of a tumor-targeting chimeric receptor expressed on an immunomodulatory cell.

[0093] In some embodiments, the one or more intracellular signaling domains comprise at least one ITIM and at least one phosphatase. In some embodiments, the phosphatase is a protein tyrosine phosphatase (PTP). In some embodiments, the one or more intracellular signaling domains are each derived from a protein selected from the group consisting of PTPRO and PTPRZ1.

[0094] In some embodiments, one of the one or more intracellular signaling domains is derived from PTPRO. In some embodiments, the intracellular signaling domain is LRKKHLQMARECGAGTFVNFASLERDGKLPYNWRRSIFAFLTLLPSCLWTDYLLAFYINPWSKNGLKKRKLTNPVQLDDFDAYIKDMAKDSDYKFSLQFEELKLIGLDIPHFAADLPLNRCKNRYTNILPYDFSRVRLVSMNEEEGADYINANYIPGYNSPQEYIATQGPLPETRNDFWKMVLQQKSQIIVMLTQCNEKRRVKCDHYWPFTEEPIAYGDITVEMISEEEQDDWACRHFRINYADEMQD It comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VMHFNYTAWPDHGVPTANAAESILQFVHMVRQQATKSKGPMIIHCSAGVGRTGTFIALDRLLQHIRDHEFVDILGLVSEMRSYRMSMVQTEEQYIFIHQCVQLMWMKKKQQFCISDVIYENVSKS (SEQ ID NO: 7).In some embodiments, the intracellular signaling domain comprises the amino acid sequence of LRKKHLQMARECGAGTFVNFASLERDGKLPYNWRRSIFAFLTLLPSCLWTDYLLAFYINPWSKNGLKKRKLTNPVQLDDFDAYIKDMAKDSDYKFSLQFEELKLIGLDIPHFAADLPLNRCKNRYTNILPYDFSRVRLVSMNEEEGADYINANYIPGYNSPQEYIATQGPLPETRNDFWKMVLQQKSQIIVMLTQCNEKRRVKCDHYWPFTEEPIAYGDITVEMISEEEQDDWACRHFRINYADEMQDVMHFNYTAWPDHGVPTANAAESILQFVHMVRQQATKSKGPMIIHCSAGVGRTGTFIALDRLLQHIRDHEFVDILGLVSEMRSYRMSMVQTEEQYIFIHQCVQLMWMKKKQQFCISDVIYENVSKS (SEQ ID NO: 7).

[0095] In some embodiments, one of the one or more intracellular signaling domains is derived from PTPRZ1. In some embodiments, the intracellular signaling domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to (SEQ ID NO:8).In some embodiments, the intracellular signaling domain comprises the amino acid sequence of (SEQ ID NO: 8).

[0096] In some embodiments, the chimeric inhibitory receptor comprises at least one ITSM. In some embodiments, the one or more intracellular signaling domains are each derived from a protein selected from the group consisting of SLAMF1 and SLAMF5.

[0097] In some embodiments, one of the one or more intracellular signaling domains is derived from SLAMF1. In some embodiments, the intracellular signaling domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to QLRRRGKTNHYQTTVEKKSLTIYAQVQKPGPLQKKLDSFPAQDPCTTIYVAATEPVPESVQETNSITVYASVTLPES (SEQ ID NO: 10). In some embodiments, the intracellular signaling domain comprises the amino acid sequence of QLRRRGKTNHYQTTVEKKSLTIYAQVQKPGPLQKKLDSFPAQDPCTTIYVAATEPVPESVQETNSITVYASVTLPES (SEQ ID NO: 10).

[0098] In some embodiments, one of the one or more intracellular signaling domains is derived from SLAMF5. In some embodiments, the intracellular signaling domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to RLFKRRQGRIFPEGSCLNTFTKNPYAASKKTIYTYIMASRNTQPAESRIYDEILQSKVLPSKEEPVNTVYSEVQFADKMGKASTQDSKPPGTSSYEIVI (SEQ ID NO: 11). In some embodiments, the intracellular signaling domain comprises the amino acid sequence of RLFKRRQGRIFPEGSCLNTFTKNPYAASKKTIYTYIMASRNTQPAESRIYDEILQSKVLPSKEEPVNTVYSEVQFADKMGKASTQDSKPPGTSSYEIVI (SEQ ID NO: 11).

[0099] In some embodiments, the transmembrane domain is derived from a protein selected from the group consisting of CD8, CD28, CD3ζ, CD4, 4-IBB, OX40, ICOS, 2B4, CD25, CD7, LAX, LAT, LIR1, PCAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0100] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from PECAM-1. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to GLIAVVIIGVIIALLIIAA (SEQ ID NO: 24). In some embodiments, the transmembrane domain comprises the amino acid sequence of GLIAVVIIGVIIALLIIAA (SEQ ID NO: 24).

[0101] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from LIR1. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VIGILVAVILLLLLLLLLFLI (SEQ ID NO: 25). In some embodiments, the transmembrane domain comprises the amino acid sequence of VIGILVAVILLLLLLLLLFLI (SEQ ID NO: 25).

[0102] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from IRTA2. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VAGGLLSIAGLAAGALLLYCW (SEQ ID NO: 26). In some embodiments, the transmembrane domain comprises the amino acid sequence of VAGGLLSIAGLAAGALLLYCW (SEQ ID NO: 26).

[0103] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from IRTA4. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LWGLFGVLGFTGVALLLYALF (SEQ ID NO: 27). In some embodiments, the transmembrane domain comprises the amino acid sequence of LWGLFGVLGFTGVALLLYALF (SEQ ID NO: 27).

[0104] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from NKIR. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VLLPLIFTILLLLLVAASLLA (SEQ ID NO: 28). In some embodiments, the transmembrane domain comprises the amino acid sequence of VLLPLIFTILLLLLVAASLLA (SEQ ID NO: 28).

[0105] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from IL1RAP. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VLLVVILIVVYHVYWLEMVLF (SEQ ID NO: 29). In some embodiments, the transmembrane domain comprises the amino acid sequence of VLLVVILIVVYHVYWLEMVLF (SEQ ID NO: 29).

[0106] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from PTPRO. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to ISVLAILSTLLIGLLLVTLII (SEQ ID NO: 30). In some embodiments, the transmembrane domain comprises the amino acid sequence of ISVLAILSTLLIGLLLVTLII (SEQ ID NO: 30).

[0107] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from PTPRZ1. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to AVIPLVIVSALTFICLVVLVGILIYW (SEQ ID NO: 31). In some embodiments, the transmembrane domain comprises the amino acid sequence of AVIPLVIVSALTFICLVVLVGILIYW (SEQ ID NO: 31).

[0108] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from TLT1. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LIWGAVLLVGLLVAAVVLFAV (SEQ ID NO: 32). In some embodiments, the transmembrane domain comprises the amino acid sequence of LIWGAVLLVGLLVAAVVLFAV (SEQ ID NO: 32).

[0109] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from SLAMF1. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to WAVYAGLLGGVIMILIMVVIL (SEQ ID NO: 33). In some embodiments, the transmembrane domain comprises the amino acid sequence of WAVYAGLLGGVIMILIMVVIL (SEQ ID NO: 33).

[0110] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from SLAMF5. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LLSVLAMFFLLVLILSSVFLF (SEQ ID NO: 34). In some embodiments, the transmembrane domain comprises the amino acid sequence of LLSVLAMFFLLVLILSSVFLF (SEQ ID NO: 34).

[0111] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from PCDHGC3. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LLLSLILVSVGFVVTVFGVII (SEQ ID NO: 139). In some embodiments, the transmembrane domain comprises the amino acid sequence of LLLSLILVSVGFVVTVFGVII (SEQ ID NO: 139).

[0112] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from LIFR. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VGLIIAILIPVAVAVIVGVVTSILC (SEQ ID NO: 140). In some embodiments, the transmembrane domain comprises the amino acid sequence of VGLIIAILIPVAVAVIVGVVTSILC (SEQ ID NO: 140).

[0113] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from ERMAP. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VALAVILPVLVLLIMVCLCLI (SEQ ID NO: 141). In some embodiments, the transmembrane domain comprises the amino acid sequence of VALAVILPVLVLLIMVCLCLI (SEQ ID NO: 141).

[0114] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from IL1RAPL2. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to IELAGGLGAIFLLLVLLVVIY (SEQ ID NO: 142). In some embodiments, the transmembrane domain comprises the amino acid sequence of IELAGGLGAIFLLLVLLVVIY (SEQ ID NO: 142).

[0115] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from CDH5. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to AVVAILLCILTITVITLLIFL (SEQ ID NO: 143). In some embodiments, the transmembrane domain comprises the amino acid sequence of AVVAILLCILTITVITLLIFL (SEQ ID NO: 143).

[0116] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from MPZL1. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to FPVWVVVGIVTAVVLGLTLLI (SEQ ID NO: 144). In some embodiments, the transmembrane domain comprises the amino acid sequence of FPVWVVVGIVTAVVLGLTLLI (SEQ ID NO: 144).

[0117] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from MPZ. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to YGVVLGAVIGGVLGVVLLLLLLFYVV (SEQ ID NO: 145). In some embodiments, the transmembrane domain comprises the amino acid sequence of YGVVLGAVIGGVLGVVLLLLLLFYVV (SEQ ID NO: 145).

[0118] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from FCGR2B. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SSSPMGIIVAVVTGIAVAAIVAA (SEQ ID NO: 146). In some embodiments, the transmembrane domain comprises the amino acid sequence of SSSPMGIIVAVVTGIAVAAIVAA (SEQ ID NO: 146).

[0119] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from SIGLEC-6. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LGAVWGASITTLVFLCVCFIF (SEQ ID NO: 147). In some embodiments, the transmembrane domain comprises the amino acid sequence of LGAVWGASITTLVFLCVCFIF (SEQ ID NO: 147).

[0120] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from MPIG6B. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LLIPLLGAGLVLGLGALGLVW (SEQ ID NO: 148). In some embodiments, the transmembrane domain comprises the amino acid sequence of LLIPLLGAGLVLGLGALGLVW (SEQ ID NO: 148).

[0121] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from VSIG4. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VFAIILIISLCCMVVFTMAYI (SEQ ID NO: 149). In some embodiments, the transmembrane domain comprises the amino acid sequence of VFAIILIISLCCMVVFTMAYI (SEQ ID NO: 149).

[0122] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from SIGLEC-12. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to FGGAGATALVFLYFCIIFVVV (SEQ ID NO: 150). In some embodiments, the transmembrane domain comprises the amino acid sequence of FGGAGATALVFLYFCIIFVVV (SEQ ID NO: 150).

[0123] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from LIR8. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VVTGVSVAFVLLLFLLLFLLL (SEQ ID NO: 151). In some embodiments, the transmembrane domain comprises the amino acid sequence of VVTGVSVAFVLLLFLLLFLLL (SEQ ID NO: 151).

[0124] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from IRTA1. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VAAGATGGLLSALLLAVALLF (SEQ ID NO: 152). In some embodiments, the transmembrane domain comprises the amino acid sequence of VAAGATGGLLSALLLAVALLF (SEQ ID NO: 152).

[0125] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from KIR2DL4. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to AVIRYSVAIILFTILPFFLLH (SEQ ID NO: 153). In some embodiments, the transmembrane domain comprises the amino acid sequence of AVIRYSVAIILFTILPFFLLH (SEQ ID NO: 153).

[0126] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from KIR2DL5. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LHILIGTSVAIILFIILFFFL (SEQ ID NO: 154). In some embodiments, the transmembrane domain comprises the amino acid sequence of LHILIGTSVAIILFIILFFFL (SEQ ID NO: 154).

[0127] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from SIGLEC-7. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to GAVGGAGATALVFLSFCVIFIVV (SEQ ID NO: 155). In some embodiments, the transmembrane domain comprises the amino acid sequence of GAVGGAGATALVFLSFCVIFIVV (SEQ ID NO: 155).

[0128] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from FCRH3. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to AAGITGLVLSILVLAAAAALL (SEQ ID NO: 156). In some embodiments, the transmembrane domain comprises the amino acid sequence of AAGITGLVLSILVLAAAAALL (SEQ ID NO: 156).

[0129] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from PCDHGC5. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LIVALATVSLLSLVTFTFLSA (SEQ ID NO: 157). In some embodiments, the transmembrane domain comprises the amino acid sequence of LIVALATVSLLSLVTFTFLSA (SEQ ID NO: 157).

[0130] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from CDH11. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to GALIAILACIVILLVIVVLFVTL (SEQ ID NO: 158). In some embodiments, the transmembrane domain comprises the amino acid sequence of GALIAILACIVILLVIVVLFVTL (SEQ ID NO: 158).

[0131] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from IMPG2. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VIIGITIASVVGLLVIFSAII (SEQ ID NO: 159). In some embodiments, the transmembrane domain comprises the amino acid sequence of VIIGITIASVVGLLVIFSAII (SEQ ID NO: 159).

[0132] In some embodiments, the chimeric inhibitory receptor comprises a transmembrane domain derived from DSCAM. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LVTISCILVGVLLLFVLLLVV (SEQ ID NO: 160). In some embodiments, the transmembrane domain comprises the amino acid sequence of LVTISCILVGVLLLFVLLLVV (SEQ ID NO: 160).

[0133] In some embodiments, the protein is not expressed on the target tumor.

[0134] In some embodiments, the protein is expressed on a non-tumor cell.

[0135] In some embodiments, the protein is expressed on a non-tumor cell derived from a tissue selected from the group consisting of brain, neuronal tissue, endocrine, endothelial, bone, bone marrow, immune system, muscle, lung, liver, gallbladder, pancreas, gastrointestinal tract, kidney, urinary bladder, male reproductive organs, female reproductive organs, adipose, soft tissue, and skin.

[0136] In some embodiments, the extracellular protein binding domain comprises a ligand binding domain. In some embodiments, the extracellular protein binding domain comprises a receptor binding domain. In some embodiments, the extracellular protein binding domain comprises an antigen binding domain. In some embodiments, the antigen binding domain comprises an antibody, an antigen-binding fragment of an antibody, an F(ab) fragment, an F(ab') fragment, a single-chain variable fragment (scFv), or a single-domain antibody (sdAb).

[0137] In some embodiments, the antigen-binding domain comprises a single-chain variable fragment (scFv). In some embodiments, each scFv comprises a heavy chain variable domain (VH) and a light chain variable domain (VL). In some embodiments, the VH and VL are separated by a peptide linker. In some embodiments, the peptide linker comprises an amino acid sequence selected from the group consisting of: GGS (SEQ ID NO: 47), GGSGGS (SEQ ID NO: 48), GGSGGSGGS (SEQ ID NO: 49), GGSGGSGGSGGS (SEQ ID NO: 50), GGSGGSGSGSGGS (SEQ ID NO: 51), GGGS (SEQ ID NO: 52), GGGSGGGS (SEQ ID NO: 53), GGGSGGGSGGGS (SEQ ID NO: 54), GGGSGGGSGGGSGGGS (SEQ ID NO: 55), GGGSGGGSGGGSGGGSGGGS (SEQ ID NO: 56), GGGGS (SEQ ID NO: 57), GGGGSGGGGS (SEQ ID NO: 58). 58), GGGGSGGGGSGGGGS (SEQ ID NO: 59), GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 60), GGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 61), GGGSGGGGSGGGGGSQSV (SEQ ID NO: 63), GSTSGSGKPGSGEGSTKG (SEQ ID NO: 64), SGGGGSGGGGSGGGGSGGGGSGGGSLQ (SEQ ID NO: 65), and TTTPAPRPPTPAPTIALQPLSLRPEACRPAAGGAVHTRGLDFACDQTTPGERSSLPAFYPGTSGSCSGCGSLSLP (SEQ ID NO: 62).

[0138] In some embodiments, the scFv comprises the structure VH-L-VL or VL-L-VH, where VH is a heavy chain variable domain, L is a peptide linker, and VL is a light chain variable domain.

[0139] In some embodiments, the transmembrane domain is physically linked to the extracellular protein binding domain. In some embodiments, one of the one or more intracellular signaling domains is physically linked to the transmembrane domain. In some embodiments, the transmembrane domain is physically linked to the extracellular protein binding domain and one of the one or more intracellular signaling domains is physically linked to the transmembrane domain.

[0140] In some embodiments, the extracellular protein binding domain has a high binding affinity. In some embodiments, the extracellular protein binding domain has a low binding affinity.

[0141] In some embodiments, the chimeric inhibitory receptor can suppress cytokine production from activated immunoregulatory cells.

[0142] In some embodiments, the chimeric inhibitory receptor can suppress a cell-mediated immune response against a target cell, where the immune response is induced by the activation of immunoregulatory cells.

[0143] In some embodiments, the target cell is a tumor cell.

[0144] In some embodiments, the one or more intracellular signaling domains comprise one or more modifications. In some embodiments, the one or more modifications modulate the sensitivity of the chimeric inhibitory receptor compared to an otherwise identical, unmodified receptor. In some embodiments, the one or more modifications increase the sensitivity of the chimeric inhibitory receptor compared to an otherwise identical, unmodified receptor. In some embodiments, the one or more modifications decrease the sensitivity of the chimeric inhibitory receptor compared to an otherwise identical, unmodified receptor. In some embodiments, the one or more modifications modulate the potency of the chimeric inhibitory receptor compared to an otherwise identical, unmodified receptor. In some embodiments, the one or more modifications increase the potency of the chimeric inhibitory receptor compared to an otherwise identical, unmodified receptor. In some embodiments, the one or more modifications decrease the potency of the chimeric inhibitory receptor compared to an otherwise identical, unmodified receptor. In some embodiments, the one or more modifications modulate primary prevention, attenuation, or inhibition of activation of the tumor-targeting chimeric receptor when expressed on an immunomodulatory cell compared to an otherwise identical, unmodified receptor. In some embodiments, the one or more modifications decrease basal prevention, attenuation, or inhibition compared to an otherwise identical, unmodified receptor, hi some embodiments, the one or more modifications increase basal prevention, attenuation, or inhibition compared to an otherwise identical, unmodified receptor.

[0145] In some embodiments, the chimeric inhibitory receptor further comprises a spacer region disposed between the extracellular protein binding domain and the transmembrane domain and operably linked to each of the extracellular protein binding domain and the transmembrane domain. In some embodiments, the chimeric inhibitory receptor further comprises a spacer region disposed between the extracellular protein binding domain and the transmembrane domain and physically linked to each of the extracellular protein binding domain and the transmembrane domain. In some embodiments, the spacer region is derived from a protein selected from the group consisting of CD8α, CD4, CD7, CD28, IgG1, IgG4, FcγRIIIα, LNGFR, and PDGFR.

[0146] In some embodiments, the spacer region is selected from the group consisting of TTTPAPRPPTPAPTIALQPLSLRPEACRPAAGGAVHTRGLDFACD (SEQ ID NO: 73), ALSNSIMYFSHFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD (SEQ ID NO: 77), AAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKP (SEQ ID NO: 67), ESKYGPPCPSCP (SEQ ID NO: 68), ESKYGPPAPSAP (SEQ ID NO: 69), ESK YGPPCPPCP (SEQ ID NO: 70), EPKSCDKTHTCP (SEQ ID NO: 71), AAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRN (SEQ ID NO: 72), ACPTGLYTHSGECCKACNLGEGVAQPCGANQTVCEPCLDSVTFSDVVSATEPCKPCTECVGLQSMSAPCVEADDAVCRCAYGYYQDETTGRCEACRVCEAGSGLVFSCQDKQ NTVCEECPDGTYSDEADAEC (SEQ ID NO: 74), ACPTGLYTHSGECCKACNLGEGVAQPCGANQTVC (SEQ ID NO: 75), AVGQDTQEVIVVPHSLPFKV (SEQ ID NO: 76), ESKYGPPCPSCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 183), and ESKYGPPCPSCPGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 184).

[0147] In some embodiments, the spacer region modulates the sensitivity of the chimeric inhibitory receptor compared to an otherwise identical chimeric inhibitory receptor lacking the spacer region. In some embodiments, the spacer region increases the sensitivity of the chimeric inhibitory receptor compared to an otherwise identical chimeric inhibitory receptor lacking the spacer region. In some embodiments, the spacer region decreases the sensitivity of the chimeric inhibitory receptor compared to an otherwise identical chimeric inhibitory receptor lacking the spacer region. In some embodiments, the spacer region modulates the potency of the chimeric inhibitory receptor compared to an otherwise identical chimeric inhibitory receptor lacking the spacer region. In some embodiments, the spacer region increases the potency of the chimeric inhibitory receptor compared to an otherwise identical chimeric inhibitory receptor lacking the spacer region. In some embodiments, the spacer region decreases the potency of the chimeric inhibitory receptor compared to an otherwise identical chimeric inhibitory receptor lacking the spacer region. In some embodiments, the spacer region modulates basal prevention, attenuation, or inhibition of activation of the tumor-targeting chimeric receptor when expressed on an immunomodulatory cell compared to an otherwise identical chimeric inhibitory receptor lacking the spacer region. In some embodiments, the spacer region decreases basal prevention, attenuation, or inhibition compared to an otherwise identical chimeric inhibitory receptor lacking the spacer region. In some embodiments, the spacer region increases basal prevention, attenuation, or inhibition compared to an otherwise identical chimeric inhibitory receptor lacking the spacer region. In some embodiments, the chimeric inhibitory receptor further comprises an intracellular spacer region disposed between the transmembrane domain and one of the one or more intracellular signaling domains and operably linked to each of the transmembrane domain and one of the one or more intracellular signaling domains. In some embodiments, the chimeric inhibitory receptor further comprises an intracellular spacer region disposed between the transmembrane domain and one of the one or more intracellular signaling domains and physically linked to each of the transmembrane domain and one of the one or more intracellular signaling domains.In some embodiments, the intracellular spacer region modulates the sensitivity of the chimeric inhibitory receptor compared to an otherwise identical chimeric inhibitory receptor lacking the intracellular spacer region, hi some embodiments, the intracellular spacer region increases the sensitivity of the chimeric inhibitory receptor compared to an otherwise identical chimeric inhibitory receptor lacking the intracellular spacer region.

[0148] In some embodiments, the intracellular spacer region reduces the sensitivity of the chimeric inhibitory receptor compared to an otherwise identical chimeric inhibitory receptor lacking the intracellular spacer region. In some embodiments, the intracellular spacer region modulates the potency of the chimeric inhibitory receptor compared to an otherwise identical chimeric inhibitory receptor lacking the intracellular spacer region. In some embodiments, the intracellular spacer region increases the potency of the chimeric inhibitory receptor compared to an otherwise identical chimeric inhibitory receptor lacking the intracellular spacer region. In some embodiments, the intracellular spacer region reduces the potency of the chimeric inhibitory receptor compared to an otherwise identical chimeric inhibitory receptor lacking the intracellular spacer region. In some embodiments, the intracellular spacer region modulates basal prevention, attenuation, or inhibition of activation of the tumor-targeting chimeric receptor when expressed on immunomodulatory cells compared to an otherwise identical chimeric inhibitory receptor lacking the intracellular spacer region. In some embodiments, the intracellular spacer region reduces basal prevention, attenuation, or inhibition compared to an otherwise identical chimeric inhibitory receptor lacking the intracellular spacer region. In some embodiments, the intracellular spacer region increases basal prevention, attenuation, or inhibition compared to an otherwise identical chimeric inhibitory receptor lacking the intracellular spacer region.

[0149] In some embodiments, the inhibitory chimeric receptor further comprises an enzyme inhibitory domain, which in some embodiments can also prevent, attenuate, or inhibit activation of the tumor-targeting chimeric receptor when expressed on an immunomodulatory cell, compared to an otherwise identical chimeric inhibitory receptor lacking the enzyme inhibitory domain.

[0150] In some embodiments, the enzyme inhibitory domain comprises an enzyme catalytic domain, hi some embodiments, the enzyme catalytic domain is derived from an enzyme selected from the group consisting of CSK, SHP-1, PTEN, CD45, CD148, PTP-MEG1, PTP-PEST, c-CBL, CBL-b, PTPN22, LAR, PTPH1, SHIP-1, and RasGAP.

[0151] In some embodiments, the enzyme inhibitory domain comprises one or more modifications that modulate basic prevention, attenuation, or inhibition.

[0152] In some embodiments, the one or more modifications decrease basal prevention, attenuation, or inhibition compared to an otherwise identical enzyme inhibitory domain lacking the one or more modifications, hi some embodiments, the one or more modifications increase basal prevention, attenuation, or inhibition compared to an otherwise identical enzyme inhibitory domain lacking the one or more modifications.

[0153] In some embodiments, the tumor-targeting chimeric receptor is a chimeric antigen receptor (CAR) or an engineered T cell receptor (TCR). In some embodiments, the immunoregulatory cell is selected from the group consisting of T cells, CD8+ T cells, CD4+ T cells, gamma-delta T cells, cytotoxic T lymphocytes (CTLs), regulatory T cells, virus-specific T cells, natural killer T (NKT) cells, natural killer (NK) cells, B cells, tumor-infiltrating lymphocytes (TILs), innate lymphocytes, mast cells, eosinophils, basophils, neutrophils, myeloid cells, macrophages, monocytes, dendritic cells, ESC-derived cells, and iPSC-derived cells. In some embodiments, the immunoregulatory cell is a natural killer (NK) cell.

[0154] Another embodiment of the present disclosure provides a composition comprising a chimeric inhibitory receptor of the present disclosure and a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, or a combination thereof.

[0155] Another embodiment of the present disclosure provides an engineered nucleic acid encoding a chimeric inhibitory receptor of the present disclosure.

[0156] Another embodiment of the present disclosure provides an expression vector comprising an engineered nucleic acid of the present disclosure.

[0157] Another embodiment of the present disclosure provides a composition comprising an engineered nucleic acid of the present disclosure or an expression vector of the present disclosure and a pharmaceutically acceptable carrier.

[0158] Another embodiment of the present disclosure provides a production cell comprising a chimeric inhibitory receptor of the present disclosure, an engineered nucleic acid of the present disclosure, or an expression vector of the present disclosure.

[0159] Another embodiment of the present disclosure provides an isolated immunomodulatory cell comprising a chimeric inhibitory receptor of the present disclosure, an engineered nucleic acid of the present disclosure, or an expression vector of the present disclosure. In some embodiments, the cell further comprises a tumor-targeting chimeric receptor expressed on the surface of the cell. In some embodiments, upon binding of a protein to the chimeric inhibitory receptor, the chimeric inhibitory receptor prevents, attenuates, or inhibits activation of the tumor-targeting chimeric receptor compared to an otherwise identical cell lacking the chimeric inhibitory receptor.

[0160] Another embodiment of the present disclosure provides an isolated immunomodulatory cell comprising a chimeric inhibitory receptor, the chimeric inhibitory receptor comprising an extracellular protein binding domain, a transmembrane domain, the transmembrane domain operably linked to the extracellular protein binding domain, and one or more intracellular signaling domains, the one or more intracellular signaling domains operably linked to the transmembrane domain, and the one or more intracellular signaling domains are each selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, and SLAMF. In some embodiments, the chimeric inhibitory receptor is derived from a protein selected from the group consisting of: 1, sSLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM, and when the protein binds to the chimeric inhibitory receptor, the chimeric inhibitory receptor prevents, attenuates, or inhibits activation of the tumor-targeting chimeric receptor expressed on the surface of the cell. In some embodiments, the cell further comprises a tumor-targeting chimeric receptor expressed on the surface of the cell.

[0161] Another embodiment of the present disclosure provides an isolated cell comprising a chimeric inhibitory receptor, the chimeric inhibitory receptor comprising an extracellular protein binding domain, a transmembrane domain, the transmembrane domain operably linked to the extracellular protein binding domain, and one or more intracellular signaling domains, the one or more intracellular signaling domains operably linked to the transmembrane domain, and the one or more intracellular signaling domains are each selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, and SLAMF5. The tumor-targeting chimeric receptor is derived from a protein selected from the group consisting of: , PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM, and the tumor-targeting chimeric receptor is expressed on the surface of a cell, and upon binding of the protein to the chimeric inhibitory receptor, the chimeric inhibitory receptor prevents, attenuates, or inhibits activation of the tumor-targeting chimeric receptor. In some embodiments, the chimeric inhibitory receptor is recombinantly expressed. In some embodiments, the chimeric inhibitory receptor is expressed from a vector or a locus selected from the genome of the cell.

[0162] In some embodiments, the tumor-targeting chimeric receptor is a chimeric antigen receptor (CAR) or an engineered T cell receptor. In some embodiments, the tumor-targeting chimeric receptor can activate cells before the protein binds to the chimeric inhibitory receptor. In some embodiments, when the protein binds to the chimeric inhibitory receptor, the chimeric inhibitory receptor suppresses cytokine production from activated cells. In some embodiments, when the protein binds to the chimeric inhibitory receptor, the chimeric inhibitory receptor suppresses cell-mediated immune responses against target cells, where the immune response is induced by the activation of immunoregulatory cells.

[0163] In some embodiments, the transmembrane domain is physically linked to the extracellular protein binding domain. In some embodiments, the intracellular signaling domain is physically linked to the transmembrane domain. In some embodiments, the transmembrane domain is physically linked to the extracellular protein binding domain and one of the one or more intracellular signaling domains is physically linked to the transmembrane domain. In some embodiments, the target cell is a tumor cell.

[0164] In some embodiments, the cells are selected from the group consisting of T cells, CD8+ T cells, CD4+ T cells, gamma-delta T cells, cytotoxic T lymphocytes (CTLs), regulatory T cells, virus-specific T cells, natural killer T (NKT) cells, natural killer (NK) cells, B cells, tumor-infiltrating lymphocytes (TILs), innate lymphocytes, mast cells, eosinophils, basophils, neutrophils, myeloid cells, macrophages, monocytes, dendritic cells, ESC-derived cells, and iPSC-derived cells. In some embodiments, the cells are natural killer (NK) cells. In some embodiments, the cells are autologous. In some embodiments, the cells are allogeneic.

[0165] Another embodiment of the present disclosure provides a composition comprising an isolated cell of the present disclosure and a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, or a combination thereof.

[0166] Another embodiment of the present disclosure provides a method of preventing, attenuating, or inhibiting a cell-mediated immune response induced by a tumor-targeting chimeric receptor expressed on the surface of an immunomodulatory cell, comprising engineering the immunomodulatory cell to express any one of the chimeric inhibitory receptors of the present disclosure on its surface, wherein upon binding of a cognate antigen to the chimeric inhibitory receptor, the intracellular signaling domain prevents, attenuates, or inhibits activation of the tumor-targeting chimeric receptor.

[0167] Another embodiment of the present disclosure provides a method for preventing, attenuating, or inhibiting activation of a tumor-targeting chimeric receptor expressed on the surface of an immunomodulatory cell, comprising contacting an isolated cell of the present disclosure or a composition of the present disclosure with a cognate antigen of the chimeric inhibitory receptor under conditions suitable for the chimeric inhibitory receptor to bind the cognate antigen, wherein upon binding of the antigen to the chimeric inhibitory receptor, the intracellular signaling domain prevents, attenuates, or inhibits activation of the tumor-targeting chimeric receptor.

[0168] In some embodiments, the tumor-targeting chimeric receptor is a chimeric antigen receptor (CAR) or an engineered T cell receptor. In some embodiments, the CAR binds to one or more antigens expressed on the surface of tumor cells. [Brief explanation of the drawings]

[0169] These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description and accompanying drawings.

[0170] [Figure 1] FIG. 1 shows an exemplary schematic diagram of a T cell co-expressing an anti-CD19-SLAP iCAR and an anti-CD20-CD28 / CD3ζ aCAR in contact with a target cell expressing CD19 and CD20.

[0171] [Figure 2A] Figure 2A shows killing of SEM cells using NK cells expressing a combination of aCAR and iCAR with different iCAR intracellular domains. [Figure 2B] Figure 2B shows the secretion of TNF-α (TNFa) from NK cells expressing the same aCAR and iCAR.

[0172] [Figure 3-1]Figure 3 shows the expression levels of different aCAR-iCAR combinations visualized by flow cytometry. Flow cytometry to assess expression levels was performed 6 days after transduction with the aCAR-iCAR constructs. [Figure 3-2] Same as above.

[0173] [Figure 4A] Figure 4A shows CAR-specific killing of SEM cells using donor-derived NK cells transduced with aCAR and different iCAR constructs with variable intracellular domains. [Figure 4B] FIG. 4B shows the expression of interferon-γ (IFNg) in the same cells as in FIG. 4A. [Figure 4C] FIG. 4C shows the expression of TNF-α (TNFa) in the same cells as in FIG. 4A.

[0174] [Figure 5A] Figure 5A shows the characteristics of different aCAR-iCAR combinations in NK cells as determined by flow cytometry. The top panel shows the mean fluorescence intensity of aCAR / iCAR in transduced NK cells. [Figure 5B] FIG. 5B shows the characteristics of NK-mediated cell killing of SEM target cells expressing the target antigen and / or safety antigen.

[0175] [Figure 6] FIG. 6 shows the expression of VSIG2-targeting iCARs with various inhibitory ICDs in engineered NK cells and the protective effect of VSIG2-targeting iCARs on VSIG2-expressing cells. DETAILED DESCRIPTION OF THE INVENTION

[0176] Detailed Description definition Terms used in the claims and specification, unless otherwise specified, are defined as set forth below.

[0177] The term "chimeric inhibitory receptor" or "chimeric inhibitory antigen receptor" or "chimeric inhibitory receptor" as used herein refers to a polypeptide or collection of polypeptides that, when expressed in an immune effector cell, provides the cell with target cell specificity and the generation of an inhibitory intracellular signal. Chimeric inhibitory receptors typically include an extracellular protein-binding domain (e.g., an antibody fragment as an antigen-binding domain), a spacer domain, a transmembrane domain, and one or more intracellular signaling / co-signaling domains. Chimeric inhibitory receptors are sometimes referred to as "iCARs."

[0178] The term "tumor-targeted chimeric receptor" refers to an activating chimeric receptor, a tumor-targeted chimeric antigen receptor (CAR), or an engineered T cell receptor. Tumor-targeted chimeric receptors are sometimes referred to as "aCARs."

[0179] As used herein, the term "chimeric antigen receptor" or alternatively "CAR" refers to a polypeptide or set of polypeptides that, when expressed in an immune effector cell, provides the cell with specificity for a target cell and generates an intracellular signal. CARs typically comprise an extracellular protein-binding domain (e.g., an antibody fragment as the antigen-binding domain), a spacer domain, a transmembrane domain, and one or more intracellular signaling / co-signaling domains. In some embodiments, a CAR comprises at least an extracellular antigen-binding domain, a transmembrane domain, and a cytoplasmic signaling domain (also referred to herein as an "intracellular signaling domain") comprising a functional signaling domain derived from an inhibitory molecule or a stimulatory molecule and / or a costimulatory molecule. In some aspects, the set of polypeptides comprising an inhibitory chimeric receptor or a tumor-targeting chimeric receptor are contiguous with one another. In some embodiments, the inhibitory chimeric receptor or the tumor-targeting chimeric receptor further comprises a spacer domain between the extracellular antigen-binding domain and the transmembrane domain. In some embodiments, the set of polypeptides comprises a recruitment domain, such as a dimerization or multimerization domain, that allows the polypeptides to bind to one another. In some embodiments, the inhibitory chimeric receptor comprises a chimeric fusion protein comprising an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling domain comprising a functional signaling domain derived from an inhibitory molecule or a stimulatory molecule. In one aspect, the inhibitory chimeric receptor comprises a chimeric fusion protein comprising an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling domain comprising a functional inhibitory domain derived from an inhibitory molecule. In one aspect, the tumor-targeting chimeric receptor comprises a chimeric fusion protein comprising an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling domain comprising a functional signaling domain derived from a costimulatory molecule and a functional signaling domain derived from a stimulatory molecule.

[0180] As used herein, the term "intracellular signaling domain" refers to a functional domain of an inhibitory chimeric receptor or a tumor-targeting chimeric receptor located intracellularly. In some embodiments, the intracellular signaling domain is an inhibitory signaling domain. Following binding of the molecular binding domain to a protein, for example, the inhibitory signaling domain suppresses receptor signaling, while the activating signaling domain transmits a signal (e.g., a growth / survival signal) to the cell.

[0181] As used herein, the term "transmembrane domain" refers to a domain that spans a cell membrane. In some embodiments, the transmembrane domain comprises a hydrophobic alpha helix.

[0182] The term "extracellular protein binding domain" or "extracellular antigen binding domain," as used herein, typically refers to a molecular binding domain that is located outside a cell and exposed to the extracellular space, such as the ectodomain of a cellular receptor or the antigen binding domain of an antibody. An extracellular antigen binding domain can comprise any molecule (e.g., a protein or peptide) that can bind to another protein or peptide. In some embodiments, the extracellular protein binding domain or antigen binding domain comprises an antibody, an antigen-binding fragment thereof, F(ab), F(ab'), a single-chain variable fragment (scFv), or a single-domain antibody (sdAb). In some embodiments, the extracellular protein or antigen binding domain binds to a cell surface ligand (e.g., an antigen expressed on the surface of a cell, e.g., a cancer antigen or protein).

[0183] The term "tumor" refers to tumor cells and the associated tumor microenvironment (TME). In some embodiments, tumor refers to tumor cells or the tumor mass. In some embodiments, tumor refers to the tumor microenvironment.

[0184] The term "not expressed" refers to expression that is at least two-fold lower than the level of expression in non-tumor cells that would result in activation of the tumor-targeted chimeric antigen receptor. In some embodiments, expression is at least two-fold, at least three-fold, at least four-fold, at least five-fold, at least six-fold, at least seven-fold, at least eight-fold, at least nine-fold, or at least ten-fold or more lower than the level of expression in non-tumor cells that would result in activation of the tumor-targeted chimeric antigen receptor.

[0185] The term "ameliorating" refers to any therapeutically beneficial result in the treatment of a disease state, for example, a cancer disease state, including prevention, reduction in severity or progression, remission, or cure thereof.

[0186] The term "in situ" refers to processes that occur in living cells grown separately from a living organism, for example, grown in tissue culture.

[0187] The term "in vivo" refers to a process that occurs inside a living organism.

[0188] As used herein, the term "mammal" includes both humans and non-humans, including, but not limited to, humans, non-human primates, canines, felines, murines, bovines, equines, and porcines.

[0189] The term "percent identity" in the context of two or more nucleic acid or polypeptide sequences refers to two or more sequences or subsequences that, when compared and aligned for maximum correspondence, have a certain percentage of the same nucleotides or amino acid residues, as determined using one of the sequence comparison algorithms described below (e.g., BLASTP and BLASTN, or other algorithms available to those of skill in the art) or by visual inspection. Depending on the application, the percent "identity" can exist over a region of the sequences being compared, e.g., over a functional domain, or alternatively, over the entire length of the two sequences being compared.

[0190] For sequence comparison, typically, one sequence serves as a reference sequence to which a test sequence is compared. When using a sequence comparison algorithm, the test sequence and the reference sequence are input into a computer, subsequence coordinates are designated as needed, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity of the test sequence relative to the reference sequence based on the designated program parameters.

[0191] Optimal alignment of sequences for comparison can be achieved, for example, by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (see generally Ausubel et al., infra).

[0192] One example of an algorithm that is suitable for determining percent sequence identity and sequence similarity is the BLAST algorithm described in Altschul et al., J. Mol. Biol. 215:403-410 (1990). Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (www.ncbi.nlm.nih.gov / ).

[0193] The term "sufficient amount" means an amount sufficient to produce a desired effect, for example, an amount sufficient to modulate protein aggregation in a cell.

[0194] The term "therapeutically effective amount" is an amount effective to ameliorate symptoms of disease. A therapeutically effective amount can be a "prophylactically effective amount" since prevention can be considered treatment.

[0195] It must be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0196] Chimeric inhibitory receptors In one aspect, provided herein is a chimeric inhibitory receptor comprising: (i) an extracellular protein binding domain; (ii) a transmembrane domain operably linked to the extracellular protein binding domain; and (iii) one or more intracellular signaling domains operably linked to the transmembrane domain, wherein at least one of the one or more intracellular signaling domains can prevent, attenuate, or inhibit activation of a tumor-targeting chimeric receptor expressed on an immunomodulatory cell. In some embodiments, a chimeric inhibitory receptor of the present disclosure comprises two or more, three or more, four or more, or five or more intracellular signaling domains. In some embodiments, a chimeric inhibitory receptor of the present disclosure comprises one intracellular signaling domain. In some embodiments, a chimeric inhibitory receptor of the present disclosure comprises two intracellular signaling domains. In some embodiments, a chimeric inhibitory receptor of the present disclosure comprises three intracellular signaling domains. In some embodiments, a chimeric inhibitory receptor of the present disclosure comprises four intracellular signaling domains. In some embodiments, a chimeric inhibitory receptor of the present disclosure comprises five intracellular signaling domains.

[0197] Generally, inhibitory chimeric receptors or tumor-targeting chimeric receptors are designed for T cells or NK cells and are chimeras of an intracellular signaling domain and an antigen recognition domain (e.g., a single-chain fragment (scFv) of an antibody) (Enblad et al., Human Gene Therapy. 2015; 26(8): 498-505). T cells expressing chimeric antigen receptors (CARs) are known in the art as CAR T cells. Activating or tumor-targeting CARs generally induce T cell signaling pathways upon binding to their cognate ligands via the intracellular signaling domain, leading to T cell activation and immune response. Activating CARs, activating CARs, and tumor-targeting CARs are interchangeable terms.

[0198] Inhibitory chimeric receptors are generally artificial immune cell receptors engineered to recognize and bind to proteins expressed by cells. Inhibitory chimeric receptors generally recognize proteins not expressed in tumor cells, while activating or tumor-targeting chimeric receptors (e.g., aCARs) generally recognize proteins expressed in tumor cells. In some embodiments, the chimeric inhibitory receptors of the present disclosure specifically bind to one or more proteins expressed in normal cells (e.g., cells generally considered healthy) but not in tumor cells. Chimeric receptors generally comprise an antibody fragment as an extracellular protein-binding domain, a spacer or hinge domain, a hydrophobic alpha-helical transmembrane domain, and one or more intracellular signaling / co-signaling domains.

[0199] Inhibitory chimeric receptors generally follow the structure of activating CARs (aCARs), but use an inhibitory domain in the intracellular signaling domain instead of the activating signaling domain derived from the T cell receptor (TCR). The intracellular signaling / co-signaling domain is an inhibitory domain that reduces or inhibits signaling by other receptor proteins within the same cell. Inhibitory chimeric receptor cells can contain antigen-specific inhibitory receptors to block nonspecific immune activation that may result from, for example, extratumor target expression. In some embodiments, the inhibitory chimeric receptor blocks T cell responses in T cells activated by endogenous T cell receptors or either activating CARs or tumor-targeting CARs. For example, immunoregulatory cells can express both an inhibitory chimeric receptor that recognizes a non-tumor protein target and a tumor-targeting chimeric receptor that recognizes a tumor protein. When such immunoregulatory cells contact tumor cells, only the tumor-targeting receptor recognizes, binds to, and is activated with its cognate ligand, leading to the induction of cell signaling pathways and immune cell activation. In contrast, when immunomodulatory cells contact non-tumor targets, the inhibitory chimeric receptor binds to its cognate ligand and suppresses or blocks signaling induced by activation of the tumor-targeted chimeric receptor. Thus, immunomodulatory cells can be engineered so that immune signaling occurs only when the cells contact tumor cells.

[0200] The inhibitory chimeric receptors of the present disclosure can inhibit the function of aCAR through a mechanism that attenuates downstream signaling of aCAR. The inhibitory chimeric receptors can contain an inhibitory tyrosine-based inhibitory motif (ITIM), an inhibitory tyrosine-based switch motif (ITSM), or a phosphatase such as a protein tyrosine phosphatase (PTP). An ITIM typically contains an amino acid motif of S / I / V / LxYxxI / V / L, where x is any amino acid, Y is a tyrosine residue that can be phosphorylated, S is the amino acid serine, I is the amino acid isoleucine, and V is the amino acid valine. The ITIM recruits an SH2 domain-containing phosphatase to target immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors (aCARs), inhibiting cell activation and resulting in the inhibition of aCAR within the cells. The ITSM can deliver an activating or inhibitory signal. The PTP can remove phosphate from phosphorylated tyrosine residues, thereby regulating intracellular signaling.

[0201] In some embodiments, the protein bound by the inhibitory chimeric receptor is not expressed on the target tumor, ie, expression is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-fold or more lower than expression levels in non-tumor cells that result in activation of the tumor-targeted chimeric antigen receptor.

[0202] In some embodiments, the protein bound by the inhibitory chimeric receptor is expressed on a non-tumor cell.

[0203] In some embodiments, the protein bound by the inhibitory chimeric receptor is expressed on a non-tumor cell derived from a tissue selected from the group consisting of brain, neuronal tissue, endocrine, endothelial, bone, bone marrow, immune system, muscle, lung, liver, gallbladder, pancreas, gastrointestinal tract, kidney, urinary bladder, male reproductive organs, female reproductive organs, adipose, soft tissue, and skin.

[0204] Intracellular signaling domains The inhibitory chimeric receptors of the present disclosure comprise an intracellular signaling domain that can prevent, attenuate, or inhibit activation of a tumor-targeting chimeric receptor expressed on an immunomodulatory cell. In some embodiments, the chimeric inhibitory receptor comprises one or more intracellular signaling domains. In some embodiments, the one or more intracellular signaling domains comprise at least one ITIM, at least one ITSM, at least one phosphatase, or any combination thereof. In some embodiments, the one or more intracellular signaling domains comprise at least one ITIM. In some embodiments, the at least one intracellular signaling domain comprises at least one ITSM. In some embodiments, the at least one intracellular signaling domain comprises at least one phosphatase. In some embodiments, the at least one intracellular domain comprises at least one ITIM and at least one phosphatase. In some embodiments, the at least one intracellular domain comprises at least one ITIM and at least one ITSM. In some embodiments, the at least one intracellular domain comprises at least one ITSM and at least one phosphatase. In some embodiments, the phosphatase is a protein tyrosine phosphatase.

[0205] In some embodiments, the intracellular signaling domain comprises one or more modifications. In some embodiments, the one or more modifications modulate the sensitivity of the chimeric inhibitory receptor compared to an otherwise identical, unmodified receptor. In some embodiments, the one or more modifications increase the sensitivity of the chimeric inhibitory receptor compared to an otherwise identical, unmodified receptor. In some embodiments, the one or more modifications decrease the sensitivity of the chimeric inhibitory receptor compared to an otherwise identical, unmodified receptor. In some embodiments, the one or more modifications modulate the potency of the chimeric inhibitory receptor compared to an otherwise identical, unmodified receptor. In some embodiments, the one or more modifications increase the potency of the chimeric inhibitory receptor compared to an otherwise identical, unmodified receptor. In some embodiments, the one or more modifications decrease the potency of the chimeric inhibitory receptor compared to an otherwise identical, unmodified receptor.

[0206] In some embodiments, the one or more modifications modulate basal prevention, attenuation, or inhibition of activation of a tumor-targeting chimeric receptor expressed on an immunomodulatory cell compared to an otherwise identical, unmodified receptor. In some embodiments, the one or more modifications decrease basal prevention, attenuation, or inhibition compared to an otherwise identical, unmodified receptor. In some embodiments, the one or more modifications increase basal prevention, attenuation, or inhibition compared to an otherwise identical, unmodified receptor.

[0207] Inhibitory domain In some embodiments, the inhibitory intracellular signaling domain is derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM. In some embodiments, the inhibitory intracellular signaling domain is a PECAM-1 domain. In some embodiments, the inhibitory intracellular signaling domain is a CD72 domain. In some embodiments, the inhibitory intracellular signaling domain is an IRTA2 domain. In some embodiments, the inhibitory intracellular signaling domain is an IRTA4 domain. In some embodiments, the inhibitory intracellular signaling domain is an NKIR domain. In some embodiments, the inhibitory intracellular signaling domain is an IL1RAP domain. In some embodiments, the inhibitory intracellular signaling domain is a PTPRO domain. In some embodiments, the inhibitory intracellular signaling domain is a PTPRZ1 domain. In some embodiments, the inhibitory intracellular signaling domain is a TLT1 domain. In some embodiments, the inhibitory intracellular signaling domain is a SLAMF1 domain. In some embodiments, the inhibitory intracellular signaling domain is a SLAMF5 domain. In some embodiments, the inhibitory intracellular signaling domain is a PCDHGC3 domain. In some embodiments, the inhibitory intracellular signaling domain is a LIFR domain. In some embodiments, the inhibitory intracellular signaling domain is an ERMAP domain. In some embodiments, the inhibitory intracellular signaling domain is an IL1RAPL2 domain. In some embodiments, the inhibitory intracellular signaling domain is a CDH5 domain. In some embodiments, the inhibitory intracellular signaling domain is a MPZL1 domain.In some embodiments, the inhibitory intracellular signaling domain is an MPZ domain. In some embodiments, the inhibitory intracellular signaling domain is an FCGR2B domain. In some embodiments, the inhibitory intracellular signaling domain is a SIGLEC-6 domain. In some embodiments, the inhibitory intracellular signaling domain is an MPIG6B domain. In some embodiments, the inhibitory intracellular signaling domain is a VSIG4 domain. In some embodiments, the inhibitory intracellular signaling domain is a SIGLEC-12 domain. In some embodiments, the inhibitory intracellular signaling domain is an LIR8 domain. In some embodiments, the inhibitory intracellular signaling domain is an IRTA1 domain. In some embodiments, the inhibitory intracellular signaling domain is a KIR2DL4 domain. In some embodiments, the inhibitory intracellular signaling domain is a KIR2DL5 domain. In some embodiments, the inhibitory intracellular signaling domain is a SIGLEC-7 domain. In some embodiments, the inhibitory intracellular signaling domain is an FCRH3 domain. In some embodiments, the inhibitory intracellular signaling domain is a PCDHGC5 domain. In some embodiments, the inhibitory intracellular signaling domain is a CDH11 domain. In some embodiments, the inhibitory intracellular signaling domain is an IMPG2 domain. In some embodiments, the inhibitory intracellular signaling domain is a DSCAM domain.

[0208] Platelet endothelial cell adhesion molecule (PECAM-1), also known as CD31, is a cell-cell adhesion molecule involved in the activation of neutrophils, monocytes, and leukocytes. Cluster of differentiation 72 (CD72) is a regulatory protein expressed on B lymphocytes and is a negative regulator of B cell responsiveness. Immunoglobulin superfamily receptor translocation-associated 2 (IRTA2) and immunoglobulin superfamily receptor translocation-associated 4 (IRTA4) encode cell surface receptors homologous to the Fc receptor family. Natural killer inhibitory receptor (NKIR) is an inhibitory receptor present on natural killer cells.

[0209] Interleukin-1 receptor accessory protein (IL1RAP or IL1R3) is a component of the interleukin-1 receptor complex and initiates signal transduction upon binding to IL-1. Receptor tyrosine-protein phosphatase O (PTPRO or GLEPP1) is a receptor protein tyrosine phosphatase involved in signal transduction in immune cells. Receptor tyrosine-protein phosphatase zeta (PTPRZ1 or phosphacan) encodes a single-pass type I membrane protein containing two cytoplasmic tyrosine phosphatase domains, an alpha-anhydroenzyme domain, and a fibronectin III domain. TREM-like transcript-1 (TLT-1) is a membrane receptor belonging to the family of receptors containing immunoreceptor tyrosine-based inhibitory motifs (ITIMs). SLAMF5 belongs to the signaling lymphocyte-activation molecule family (SLAMF) of receptors. It is a cell surface receptor regulator of autophagy. Protocadherin gamma-C3 (PCDHGC3) mediates cell-cell adhesion and belongs to the larger cadherin superfamily of proteins containing immunoglobulin-like structures. Leukemia inhibitory factor receptor (LIFR) is a receptor protein whose signaling can control several cellular processes, including growth and division (proliferation), maturation (differentiation), and survival. Erythrocyte membrane-associated protein (ERMAP) is a receptor protein that regulates T cell and macrophage responses. Interleukin-1 receptor accessory protein-like 2 (IL1RAPL2) is an accessory protein that is part of the interleukin-1 receptor family. CDH5 encodes VE-cadherin (also known as cadherin 5), a protein involved in calcium-dependent cell-cell adhesion. Myelin protein zero-like protein 1 (MPZL1) is a transmembrane glycoprotein that promotes cancer cell migration and is involved in extracellular matrix-induced signaling. Myelin protein zero (MPZ) is a single membrane glycoprotein expressed in cells of the myelin sheath. The Fc fragment of IgG receptor IIb (FCGR2B) is an inhibitory receptor for binding to IgG. SIGLEC-6 is an immunoreceptor that contains ITIM and ITSM motifs.Megakaryocyte and platelet inhibitory receptor G6b (MPIG6B) is an inhibitory receptor involved in hematopoietic lineage differentiation, megakaryocyte function, and platelet production. V-set and immunoglobulin domain-containing 4 (VSIG4) is structurally related to the B7 family of immune regulatory proteins and is a negative regulator of T cell responses. SIGLEC-12 is a cell surface protein containing ITIMs that recruit phosphatases that can inhibit immune cell signaling. LIR8 is a member of the leukocyte immunoglobulin-like receptor (LIR) family and is involved in regulating cellular responses. IRTA1, or FCRL4, encodes a member of the immunoglobulin receptor superfamily and is one of several Fc receptor-like glycoproteins. Killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4) is a transmembrane glycoprotein expressed on NK cells and CD8+ T cells that acts as an inhibitory receptor. KIR2DL5 is an inhibitory receptor thought to play a role in innate immune signaling. SIGLEC-7 is an inhibitory receptor expressed on NK cells. Fc receptor homolog 3 (FCRH3) belongs to the immunoglobulin receptor superfamily and plays a role in regulating the immune system. It contains both ITIM and ITAM domains. Protocadherin gamma-C5 (PCDHGC5) is a receptor molecule that plays a role in calcium-dependent cell adhesion. Cadherin-11 (CDH11) is a membrane protein involved in calcium-dependent cell-cell adhesion. Interphotoreceptor matrix proteoglycan 2 (IMPG2) is a receptor involved in photoreceptor maturation and maintenance. Down syndrome cell adhesion molecule (DSCAM) is a receptor involved in signal transduction in neuronal processes.

[0210] Exemplary inhibitory intracellular signaling domain protein sequences are shown in Table 1. Exemplary inhibitory intracellular signaling domain nucleotide sequences are shown in Table 2.

[0211] Table 1. Amino acid sequences of exemplary inhibitory intracellular domains TIFF2025526383000002.tif174152TIFF2025526383000003.tif220152TIFF2025526383000004.tif116152

[0212] Table 2. Nucleotide sequences of exemplary inhibitory intracellular domains TIFF2025526383000005.tif104152TIFF2025526383000006.tif226152TIFF2025526383000007.tif226152TIFF20255263830 00008.tif226152TIFF2025526383000009.tif227152TIFF2025526383000010.tif223152TIFF2025526383000011.tif173152

[0213] In some embodiments, one of the one or more intracellular signaling domains is derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0214] In some embodiments, the transmembrane domain is derived from the same protein as one of the one or more intracellular signaling domains, hi some embodiments, the transmembrane domain is derived from a first protein and one of the one or more intracellular signaling domains is derived from a second protein that is different from the first protein.

[0215] In some embodiments, one of the one or more intracellular signaling domains is derived from PECAM-1.

[0216] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to KCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEANSHYGHNDDVRNHAMKPINDNKEPLNSDVQYTEVQVSSAESHKDLGKKDTETVYSEVRKAVPDAVESRYSRTEGSLDGT (SEQ ID NO: 1).

[0217] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence KCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEANSHYGHNDDVRNHAMKPINDNKEPLNSDVQYTEVQVSSAESHKDLGKKDTETVYSEVRKAVPDAVESRYSRTEGSLDGT (SEQ ID NO: 1).

[0218] In some embodiments, one of the one or more intracellular signaling domains is derived from CD72.

[0219] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to MAEAITYADLRFVKAPLKKSISSRLGQDPGADDDGEITYENVQVPAVLGVPSSLASSVLGDKAAVKSEQPTASWRAVTSPAVGRILPCRTTCLRY (SEQ ID NO: 2).

[0220] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence MAEAITYADLRFVKAPLKKSISSRLGQDPGADDDGEITYENVQVPAVLGVPSSLASSVLGDKAAVKSEQPTASWRAVTSPAVGRILPCRTTCLRY (SEQ ID NO: 2).

[0221] In some embodiments, one of the one or more intracellular signaling domains is derived from IRTA2.

[0222] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LSRKAGRKPASDPARSPSDSDSQEPTYHNVPAWEELQPVYTNANPRGENVVYSEVRIIQEKKKHAVASDPRHLRNKGSPIIYSEVKVASTPVSGSLFLASSAPHR (SEQ ID NO: 3).

[0223] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence LSRKAGRKPASDPARSPSDSDSQEPTYHNVPAWEELQPVYTNANPRGENVVYSEVRIIQEKKKHAVASDPRHLRNKGSPIIYSEVKVASTPVSGSLFLASSAPHR (SEQ ID NO: 3).

[0224] In some embodiments, one of the one or more intracellular signaling domains is derived from IRTA4.

[0225] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to HKISGESSATNEPRGASRPNPQEFTYSSPTPDMEELQPVYVNVGSVDVDVVYSQVWSMQQPESSANIRTLLENKDSQVIYSSVKKS (SEQ ID NO: 4).

[0226] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence HKISGESSATNEPRGASRPNPQEFTYSSPTPDMEELQPVYVNVGSVDVDVVYSQVWSMQQPESSANIRTLLENKDSQVIYSSVKKS (SEQ ID NO: 4).

[0227] In some embodiments, one of the one or more intracellular signaling domains is derived from an NKIR.

[0228] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to WRMMKYQQKAAGMSPEQVLQPLEGDLCYADLTLQLAGTSPQKATTKLSSAQVDQVEVEYVTMASLPKEDISYASLTLGAEDQEPTYCNMGHLSSHLPGRGPEEPTEYSTISRP (SEQ ID NO: 5).

[0229] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence WRMMKYQQKAAGMSPEQVLQPLEGDLCYADLTLQLAGTSPQKATTKLSSAQVDQVEVEYVTMASLPKEDISYASLTLGAEDQEPTYCNMGHLSSHLPGRGPEEPTEYSTISRP (SEQ ID NO: 5).

[0230] In some embodiments, one of the one or more intracellular signaling domains is derived from IL1RAP.

[0231] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to YRAHFGTDETILDGKEYDIYVSYARNAEEEEFVLLTLRGVLENEFGYKLCIFDRDSLPGGIVTDETLSFIQKSRRLLVVLSPNYVLQGTQALLELKAGLENMASRGNINVILVQYKAVKETKVKELKRAKTVLTVIKWKGEKSKYPQGRFWKQLQVAMPVKKSPRRSSSDEQGLSYSSLKNV (SEQ ID NO: 6).

[0232] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of YRAHFGTDETILDGKEYDIYVSYARNAEEEEFVLLTLRGVLENEFGYKLCIFDRDSLPGGIVTDETLSFIQKSRRLLVVLSPNYVLQGTQALLELKAGLENMASRGNINVILVQYKAVKETKVKELKRAKTVLTVIKWKGEKSKYPQGRFWKQLQVAMPVKKSPRRSSSDEQGLSYSSLKNV (SEQ ID NO: 6).

[0233] In some embodiments, one of the one or more intracellular signaling domains is derived from PTPRO.

[0234] In some embodiments, one of the one or more intracellular signaling domains is LRKKHLQMARECGAGTFVNFASLERDGKLPYNWRRSIFAFLTLLPSCLWTDYLLAFYINPWSKNGLKKRKLTNPVQLDDFDAYIKDMAKDSDYKFSLQFEELKLIGLDIPHFAADLPLNRCKNRYTNILPYDFSRVRLVSMNEEEGADYINANYIPGYNSPQEYIATQGPLPETRNDFWKMVLQQKSQIIVMLTQCNEKRRVKCDHYWPFTEEPIAYGDITVEMISEEEQDDWACRHFRINYA It comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to DEMQDVMHFNYTAWPDHGVPTANAAESILQFVHMVRQQATKSKGPMIIHCSAGVGRTGTFIALDRLLQHIRDHEFVDILGLVSEMRSYRMSMVQTEEQYIFIHQCVQLMWMKKKQQFCISDVIYENVSKS (SEQ ID NO: 7).

[0235] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of LRKKHLQMARECGAGTFVNFASLERDGKLPYNWRRSIFAFLTLLPSCLWTDYLLAFYINPWSKNGLKKRKLTNPVQLDDFDAYIKDMAKDSDYKFSLQFEELKLIGLDIPHFAADLPLNRCKNRYTNILPYDFSRVRLVSMNEEEGADYINANYIPGYNSPQEYIATQGPLPETRNDFWKMVLQQKSQIIVMLTQCNEKRRVKCDHYWPFTEEPIAYGDITVEMISEEEQDDWACRHFRINYADEMQDVMHFNYTAWPDHGVPTANAAESILQFVHMVRQQATKSKGPMIIHCSAGVGRTGTFIALDRLLQHIRDHEFVDILGLVSEMRSYRMSMVQTEEQYIFIHQCVQLMWMKKKQQFCISDVIYENVSKS (SEQ ID NO: 7).

[0236] In some embodiments, one of the one or more intracellular signaling domains is derived from PTPRZ1.

[0237] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to (SEQ ID NO:8).

[0238] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of (SEQ ID NO: 8).

[0239] In some embodiments, one of the one or more intracellular signaling domains is derived from TLT1.

[0240] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to MAKRKQGNRLGVCGRFLSSRVSGMNPSSVVHHVSDSGPAAELPLDVPHIRLDSPPSFDNTTYTSLPLDSPSGKPSLPAPSSLPPLPPKVLVCSKPVTYATVIFPGGNKGGGTSCGPAQNPPNNQTPSS (SEQ ID NO: 9).

[0241] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence MAKRKQGNRLGVCGRFLSSRVSGMNPSSVVHHVSDSGPAAELPLDVPHIRLDSPPSFDNTTYTSLPLDSPSGKPSLPAPSSLPPLPPKVLVCSKPVTYATVIFPGGNKGGGTSCGPAQNPPNNQTPSS (SEQ ID NO: 9).

[0242] In some embodiments, one of the one or more intracellular signaling domains is derived from SLAMF1.

[0243] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to QLRRRGKTNHYQTTVEKKSLTIYAQVQKPGPLQKKLDSFPAQDPCTTIYVAATEPVPESVQETNSITVYASVTLPES (SEQ ID NO: 10).

[0244] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence QLRRRGKTNHYQTTVEKKSLTIYAQVQKPGPLQKKLDSFPAQDPCTTIYVAATEPVPESVQETNSITVYASVTLPES (SEQ ID NO: 10).

[0245] In some embodiments, one of the one or more intracellular signaling domains is derived from SLAMF5.

[0246] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to RLFKRRQGRIFPEGSCLNTFTKNPYAASKKTIYTYIMASRNTQPAESRIYDEILQSKVLPSKEEPVNTVYSEVQFADKMGKASTQDSKPPGTSSYEIVI (SEQ ID NO: 11).

[0247] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence RLFKRRQGRIFPEGSCLNTFTKNPYAASKKTIYTYIMASRNTQPAESRIYDEILQSKVLPSKEEPVNTVYSEVQFADKMGKASTQDSKPPGTSSYEIVI (SEQ ID NO: 11).

[0248] In some embodiments, one of the one or more intracellular signaling domains is derived from PCDHGC3.

[0249] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to FKVYKWKQSRDLYRAPVSSLYRTPGPSLHADAVRGGLMSPHLYHQVYLTTDSRRSDPLLKKPGAASPLASRQNTLRSCDPVFYRQVLGAESAPPGQQAPPNTDWRFSQAQRPGTSGSQNGDDTGTWPNNQFDTEMLQAMILASASEAADGSSTLGGGAGTMGLSARYGPQFTLQHVPDYRQNVYIPGSNATLTNAAGKRDGKAPAGGNGNKKKSGKKEKK (SEQ ID NO: 95).

[0250] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of FKVYKWKQSRDLYRAPVSSLYRTPGPSLHADAVRGGLMSPHLYHQVYLTTDSRRSDPLLKKPGAASPLASRQNTLRSCDPVFYRQVLGAESAPPGQQAPPNTDWRFSQAQRPGTSGSQNGDDTGTWPNNQFDTEMLQAMILASASEAADGSSTLGGGAGTMGLSARYGPQFTLQHVPDYRQNVYIPGSNATLTNAAGKRDGKAPAGGNGNKKKSGKKEKK (SEQ ID NO: 95).

[0251] In some embodiments, one of the one or more intracellular signaling domains is derived from LIFR.

[0252] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to YRKREWIKETFYPDIPNPENCKALQFQKSVCEGSSALKTLEMNPCTPNNVEVLETRSAFPKIEDTEIISPVAERPEDRSDAEPENHVVVSYCPPIIEEEIPNPAADEAGGTAQVIYIDVQSMYQPQAKPEEEQENDPVGGAGYKPQMHLPINSTVEDIAAEEDLDKTAGYRPQANVNTWNLVSPDSPRSIDSNSEIVSFGSPCSINSRQFLIPPKDEDSPKSNGGGWSFTNFFQNKPND (SEQ ID NO: 96).

[0253] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of YRKREWIKETFYPDIPNPENCKALQFQKSVCEGSSALKTLEMNPCTPNNVEVLETRSAFPKIEDTEIISPVAERPEDRSDAEPENHVVVSYCPPIIEEEIPNPAADEAGGTAQVIYIDVQSMYQPQAKPEEEQENDPVGGAGYKPQMHLPINSTVEDIAAEEDLDKTAGYRPQANVNTWNLVSPDSPRSIDSNSEIVSFGSPCSINSRQFLIPPKDEDSPKSNGGGWSFTNFFQNKPND (SEQ ID NO: 96).

[0254] In some embodiments, one of the one or more intracellular signaling domains is derived from an ERMAP.

[0255] In some embodiments, one of the one or more intracellular signaling domains is WKQRRAKEKLLYEHVTEVDNLLSDHAKEKGKLHKAVKKLRSELKLKRAAANSGWRRARLHFVAVTLDPDTAHPKLILSEDQRCVRLGDRRQPVPDNPQRFDFVVSILGSEYFTTGCHYWEVYVGDKTKWILGVCSESVSRKGKVTASPANGHWLLRQSRGNEYEALTSPQTSFRLKEPPRCVGIFLDYEAGVISFYNVTNKSHIFT FTHNFSGPLRPFFEPCLHDGGKNTAPLVICSELHKSEESIVPRPEGKGHANGDVSLKVNSSLLPPKAPELKDIILSLPPDLGPALQELKAPSF (SEQ ID NO: 97) that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to FTHNFSGPLRPFFEPCLHDGGKNTAPLVICSELHKSEESIVPRPEGKGHANGDVSLKVNSSLLPPKAPELKDIILSLPPDLGPALQELKAPSF (SEQ ID NO: 97).

[0256] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of WKQRRAKEKLLYEHVTEVDNLLSDHAKEKGKLHKAVKKLRSELKLKRAAANSGWRRARLHFVAVTLDPDTAHPKLILSEDQRCVRLGDRRQPVPDNPQRFDFVVSILGSEYFTTGCHYWEVYVGDKTKWILGVCSESVSRKGKVTASPANGHWLLRQSRGNEYEALTSPQTSFRLKEPPRCVGIFLDYEAGVISFYNVTNKSHIFTFTHNFSGPLRPFFEPCLHDGGKNTAPLVICSELHKSEESIVPRPEGKGHANGDVSLKVNSSLLPPKAPELKDIILSLPPDLGPALQELKAPSF (SEQ ID NO: 97).

[0257] In some embodiments, one of the one or more intracellular signaling domains is derived from IL1RAPL2.

[0258] In some embodiments, one of the one or more intracellular signaling domains is KCYNIELMLFYRQHFGADETNDDNKEYDAYLSYTKVDQDTLDCDNPEEEQFALEVLPDVLEKHYGYKLFIPERDLIPSGTYMEDLTRYVEQSRRLIIVLTPDYILRRGWSIFELESRLHNMLVSGEIKVILIECTELKGKVNCQEVESLKRSIKLLSLIKWKGSKSSKLNSKFWKHLVYEMPIKKKEMLPRCHVLDSAEQGLFGELQPIPSI It comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to AMTSTSATLVSSQADLPEFHPSDSMQIRHCCRGYKHEIPATTLPVPSLGNHHTYCNLPLTLLNGQLPLNNTLKDTQEFHRNSSLLPLSSKELSFTSDIW (SEQ ID NO: 98).

[0259] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of KCYNIELMLFYRQHFGADETNDDNKEYDAYLSYTKVDQDTLDCDNPEEEQFALEVLPDVLEKHYGYKLFIPERDLIPSGTYMEDLTRYVEQSRRLIIVLTPDYILRRGWSIFELESRLHNMLVSGEIKVILIECTELKGKVNCQEVESLKRSIKLLSLIKWKGSKSSKLNSKFWKHLVYEMPIKKKEMLPRCHVLDSAEQGLFGELQPIPSIAMTSTSATLVSSQADLPEFHPSDSMQIRHCCRGYKHEIPATTLPVPSLGNHHTYCNLPLTLLNGQLPLNNTLKDTQEFHRNSSLLPLSSKELSFTSDIW (SEQ ID NO: 98).

[0260] In some embodiments, one of the one or more intracellular signaling domains is derived from CDH5.

[0261] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to RRRLRKQARAHGKSVPEIHEQLVTYDEEGGGEMDTTSYDVSVLNSVRRGGAKPPRPALDARPSLYAQVQKPPRHAPGAHGGPGEMAAMIEVKKDEADHDGDGPPYDTLHIYGYEGSESIAESLSSLGTDSSDSDVDYDFLNDWGPRFKMLAELYGSDPREELLY (SEQ ID NO: 99).

[0262] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of RRRLRKQARAHGKSVPEIHEQLVTYDEEGGGEMDTTSYDVSVLNSVRRGGAKPPRPALDARPSLYAQVQKPPRHAPGAHGGPGEMAAMIEVKKDEADHDGDGPPYDTLHIYGYEGSESIAESLSSLGTDSSDSDVDYDFLNDWGPRFKMLAELYGSDPREELLY (SEQ ID NO: 99).

[0263] In some embodiments, one of the one or more intracellular signaling domains is derived from MPZL1.

[0264] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SMILAVLYRRKNSKRDYTGCSTSESLSPVKQAPRKSPSDTEGLVKSLPSGSHQGPVIYAQLDHSGGHHSDKINKSESVVYADIRKN (SEQ ID NO: 100).

[0265] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence SMILAVLYRRKNSKRDYTGCSTSESLSPVKQAPRKSPSDTEGLVKSLPSGSHQGPVIYAQLDHSGGHHSDKINKSESVVYADIRKN (SEQ ID NO: 100).

[0266] In some embodiments, one of the one or more intracellular signaling domains is derived from MPZ.

[0267] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to RYCWLRRQAALQRRLSAMEKGKLHKPGKDASKRGRQTPVLYAMLDHSRSTKAVSEKKAKGLGESRKDKK (SEQ ID NO: 101).

[0268] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence RYCWLRRQAALQRRLSAMEKGKLHKPGKDASKRGRQTPVLYAMLDHSRSTKAVSEKKAKGLGESRKDKK (SEQ ID NO: 101).

[0269] In some embodiments, one of the one or more intracellular signaling domains is derived from FCGR2B.

[0270] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VVALIYCRKKRISALPGYPECREMGETLPEKPANPTNPDEADKVGAENTITYSLLMHPDALEEPDDQNRI (SEQ ID NO: 102).

[0271] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence VVALIYCRKKRISALPGYPECREMGETLPEKPANPTNPDEADKVGAENTITYSLLMHPDALEEPDDQNRI (SEQ ID NO: 102).

[0272] In some embodiments, one of the one or more intracellular signaling domains is derived from SIGLEC-6.

[0273] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to RVKTRRKKAAQPVQNTDDVNPVMVSGSRGHQHQFQTGIVSDHPAEAGPISEDEQELHYAVLHFHKVQPQEPKVTDTEYSEIKIHK (SEQ ID NO: 103).

[0274] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence RVKTRRKKAAQPVQNTDDVNPVMVSGSRGHQHQFQTGIVSDHPAEAGPISEDEQELHYAVLHFHKVQPQEPKVTDTEYSEIKIHK (SEQ ID NO: 103).

[0275] In some embodiments, one of the one or more intracellular signaling domains is derived from MPIG6B.

[0276] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to WLHRRLPPQPIRPLPRFAPLVKTEPQRPVKEEEPKIPGDLDQEPSLLYADLDHLALSRPRRLSTADPADASTIYAVVV (SEQ ID NO: 104).

[0277] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence WLHRRLPPQPIRPLPRFAPLVKTEPQRPVKEEEPKIPGDLDQEPSLLYADLDHLALSRPRRLSTADPADASTIYAVVV (SEQ ID NO: 104).

[0278] In some embodiments, one of the one or more intracellular signaling domains is derived from VSIG4.

[0279] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to MLCRKTSQQEHVYEAARAHAREANDSGETMRVAIFASGCSSDEPTSQNLGNNYSDEPCIGQEYQIIAQINGNYARLLDTVPLDYEFLATEGKSVC (SEQ ID NO: 105). In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of MLCRKTSQQEHVYEAARAHAREANDSGETMRVAIFASGCSSDEPTSQNLGNNYSDEPCIGQEYQIIAQINGNYARLLDTVPLDYEFLATEGKSVC (SEQ ID NO: 105).

[0280] In some embodiments, one of the one or more intracellular signaling domains is derived from SIGLEC-12.

[0281] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to RSCRKKSARPAVGVGDTGMEDANAVRGSASQGPLIESPADDSPPHHAPPALATPSPEEGEIQYASLSFHKARPQYPQEQEAIGYEYSEINIPK (SEQ ID NO: 106).

[0282] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of RSCRKKSARPAVGVGDTGMEDANAVRGSASQGPLIESPADDSPPHHAPPALATPSPEEGEIQYASLSFHKARPQYPQEQEAIGYEYSEINIPK (SEQ ID NO: 106).

[0283] In some embodiments, one of the one or more intracellular signaling domains is derived from LIR8.

[0284] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to RHRHQSKHRTSAHFYRPAGAAGPEPKDQGLQKRASPVADIQEEILNAAVKDTQPKDGVEMDAPAAASEAPQDVTYAQLHSLTLRREATEPPPSQEREPPAEPSIYAPLAIH (SEQ ID NO: 107).

[0285] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence RHRHQSKHRTSAHFYRPAGAAGPEPKDQGLQKRASPVADIQEEILNAAVKDTQPKDGVEMDAPAAASEAPQDVTYAQLHSLTLRREATEPPPSQEREPPAEPSIYAPLAIH (SEQ ID NO: 107).

[0286] In some embodiments, one of the one or more intracellular signaling domains is derived from IRTA1.

[0287] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to HCWRRRKSGVGFLGDETRLPPAPGPGESSHSICPAQVELQSLYVDVHPKKGDLVYSEIQTTQLGEEEEANTSRTLLEDKDVSVVYSEVKTQHPDNSAGKISSKDEES (SEQ ID NO: 108).

[0288] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of HCWRRRKSGVGFLGDETRLPPAPGPGESSHSICPAQVELQSLYVDVHPKKGDLVYSEIQTTQLGEEEEANTSRTLLEDKDVSVVYSEVKTQHPDNSAGKISSKDEES (SEQ ID NO: 108).

[0289] In some embodiments, one of the one or more intracellular signaling domains is derived from KIR2DL4.

[0290] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to RWCSKKKDAAVMNQEPAGHRTVNREDSDEQDPQEVTYAQLDHCIFTQRKITGPSQRSKRPSTDTSVCIELPNAEPRALSPAHEHHSQALMGSSRETTALSQTQLASSNVPAAGI (SEQ ID NO: 109).

[0291] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of RWCSKKKDAAVMNQEPAGHRTVNREDSDEQDPQEVTYAQLDHCIFTQRKITGPSQRSKRPSTDTSVCIELPNAEPRALSPAHEHHSQALMGSSRETTALSQTQLASSNVPAAGI (SEQ ID NO: 109).

[0292] In some embodiments, one of the one or more intracellular signaling domains is derived from KIR2DL5.

[0293] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LHCCCSNKKNAAVMDQEPAGDRTVNREDSDDQDPQEVTYAQLDHCVFTQTKITSPSQRPKTPPTDTTMYMELPNAKPRSLSPAHKHHSQALRGSSRETTALSQNRVASSHVPAAGI (SEQ ID NO: 110).

[0294] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of LHCCCSNKKNAAVMDQEPAGDRTVNREDSDDQDPQEVTYAQLDHCVFTQTKITSPSQRPKTPPTDTTMYMELPNAKPRSLSPAHKHHSQALRGSSRETTALSQNRVASSHVPAAGI (SEQ ID NO: 110).

[0295] In some embodiments, one of the one or more intracellular signaling domains is derived from SIGLEC-7.

[0296] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to RSCRKKSARPAADVGDIGMKDANTIRGSASQGNLTESWADDNPRHHGLAAHSSGEEREIQYAPLSFHKGEPQDLSGQEATNNEYSEIKIPK (SEQ ID NO: 111).

[0297] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence RSCRKKSARPAADVGDIGMKDANTIRGSASQGNLTESWADDNPRHHGLAAHSSGEEREIQYAPLSFHKGEPQDLSGQEATNNEYSEIKIPK (SEQ ID NO: 111).

[0298] In some embodiments, one of the one or more intracellular signaling domains is derived from FCRH3.

[0299] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to HYARARRKPGGLSATGTSSHSPSECQEPSSSRPSRIDPQEPTHSKPLAPMELEPMYSNVNPGDSNPIYSQIWSIQHTKENSANCPMMHQEHEELTVLYSELKKTHPDDSAGEASSRGRAHEEDDEENYENVPRVLLASDH (SEQ ID NO: 112). In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence HYARARRKPGGLSATGTSSHSPSECQEPSSSRPSRIDPQEPTHSKPLAPMELEPMYSNVNPGDSNPIYSQIWSIQHTKENSANCPMMHQEHEELTVLYSELKKTHPDDSAGEASSRGRAHEEDDEENYENVPRVLLASDH (SEQ ID NO: 112).

[0300] In some embodiments, one of the one or more intracellular signaling domains is derived from PCDHGC5.

[0301] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to KCLQGNADGDGGGGQCCRRQDSPSPDFYKQSSPNLQVSSDGTLKYMEVTLRPTDSQSHCYRTCFSPASDGSDFTFLRPLSVQQPTALALEPDAIRSRSNTLRERSQQAPPNTDWRFSQAQRPGTSGSQNGDDTGTWPNNQFDTEMLQAMILASASEAADGSSTLGGGAGTMGLSARYGPQFTLQHVPDYRQNVYIPGSNATLTNAAGKRDGKAPAGGNGNKKKSGKKEKK (SEQ ID NO: 113).

[0302] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of KCLQGNADGDGGGGQCCRRQDSPSPDFYKQSSPNLQVSSDGTLKYMEVTLRPTDSQSHCYRTCFSPASDGSDFTFLRPLSVQQPTALALEPDAIRSRSNTLRERSQQAPPNTDWRFSQAQRPGTSGSQNGDDTGTWPNNQFDTEMLQAMILASASEAADGSSTLGGGAGTMGLSARYGPQFTLQHVPDYRQNVYIPGSNATLTNAAGKRDGKAPAGGNGNKKKSGKKEKK (SEQ ID NO: 113).

[0303] In some embodiments, one of the one or more intracellular signaling domains is derived from CDH11.

[0304] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to RRQKKEPLIVFEEEDVRENIITYDDEGGGEEDTEAFDIATLQNPDGINGFIPRKDIKPEYQYMPRPGLRPAPNSVDVDDFINTRIQEADNDPTAPPYDSIQIYGYEGRGSVAGSLSSLESATTDSDLDYDYLQNWGPRFKKLADLYGSKDTFDDDS (SEQ ID NO: 114).

[0305] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of RRQKKEPLIVFEEEDVRENIITYDDEGGGEEDTEAFDIATLQNPDGINGFIPRKDIKPEYQYMPRPGLRPAPNSVDVDDFINTRIQEADNDPTAPPYDSIQIYGYEGRGSVAGSLSSLESATTDSDLDYDYLQNWGPRFKKLADLYGSKDTFDDDS (SEQ ID NO: 114).

[0306] In some embodiments, one of the one or more intracellular signaling domains is derived from IMPG2.

[0307] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to YFFIRTLQAHHDRSERESPFSGSSRQPDSLSSIENAVKYNPVYESHRAGCEKYEGPYPQHPFYSSASGDVIGGLSREEIRQMYESSELSREEIQERMRVLELYANDPEFAAFVREQQVEEV (SEQ ID NO: 115).

[0308] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of YFFIRTLQAHHDRSERESPFSGSSRQPDSLSSIENAVKYNPVYESHRAGCEKYEGPYPQHPFYSSASGDVIGGLSREEIRQMYESSELSREEIQERMRVLELYANDPEFAAFVREQQVEEV (SEQ ID NO: 115).

[0309] In some embodiments, one of the one or more intracellular signaling domains is derived from DSCAM.

[0310] In some embodiments, one of the one or more intracellular signaling domains is RRRREQRLKRLRDAKSLAEMLMSKNTRTSDTLSKQQQTLRMHIDIPRAQLLIEERDTMETIDDRSTVLLTDADFGEAAKQKSLTVTHTVHYQSVSQATGPLVDVSDARPGTNPTTRRNAKAGPTARNRYASQWTLNRPHPTISAHTLTTDWRLPTPRAAGSVDKESDSYSVSPSQDTDRARSSMVSTESASSTYEELARAYEHAKMEEQLRHAKFTITECFISDTSSEQLTAGTNEYTDSLTSSTPSESGICRF It comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to TASPPKPQDGGRVMNMAVPKAHRPGDLIHLPPYLRMDFLLNRGGPGTSRDLSLGQACLEPQKSRTLKRPTVLEPIPMEAASSASSTREGQSWQPGAVATLPQREGAELGQAAKMSSSQESLLDSRGHLKGNNPYAKSYTLV (SEQ ID NO: 116).

[0311] In some embodiments, one of the one or more intracellular signaling domains comprises the amino acid sequence of RRRREQRLKRLRDAKSLAEMLMSKNTRTSDTLSKQQQTLRMHIDIPRAQLLIEERDTMETIDDRSTVLLTDADFGEAAKQKSLTVTHTVHYQSVSQATGPLVDVSDARPGTNPTTRRNAKAGPTARNRYASQWTLNRPHPTISAHTLTTDWRLPTPRAAGSVDKESDSYSVSPSQDTDRARSSMVSTESASSTYEELARAYEHAKMEEQLRHAKFTITECFISDTSSEQLTAGTNEYTDSLTSSTPSESGICRFTASPPKPQDGGRVMNMAVPKAHRPGDLIHLPPYLRMDFLLNRGGPGTSRDLSLGQACLEPQKSRTLKRPTVLEPIPMEAASSASSTREGQSWQPGAVATLPQREGAELGQAAKMSSSQESLLDSRGHLKGNNPYAKSYTLV (SEQ ID NO: 116).

[0312] In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 1. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO:2. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 3. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO:4. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO:7.In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 8. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO:9. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 10. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 11. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO:95.In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 96. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO:97. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 98. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO:99. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO:100.In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 101. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 102. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 103. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 104. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO:105.In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 106. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 107. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 108. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 109. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO:110.In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 112. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 113 ... and / or an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 114. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 115. In some embodiments, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO:116.

[0313] In some embodiments, the transmembrane domain and one of the one or more intracellular signaling domains are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and one of the one or more intracellular signaling domains is derived from a second protein that is different from the first protein.

[0314] Enzyme Inhibitory Domain In some embodiments, the inhibitory chimeric receptor comprises an enzyme inhibitory domain, which in some embodiments can also prevent, attenuate, or inhibit activation of the chimeric receptor when expressed on an immunomodulatory cell, relative to an otherwise identical chimeric inhibitory receptor lacking the enzyme inhibitory domain.

[0315] In some embodiments, the enzyme inhibitory domain comprises an enzyme catalytic domain, hi some embodiments, the enzyme catalytic domain is derived from an enzyme selected from the group consisting of CSK, SHP-1, PTEN, CD45, CD148, PTP-MEG1, PTP-PEST, c-CBL, CBL-b, PTPN22, LAR, PTPH1, SHIP-1, and RasGAP.

[0316] In some embodiments, the enzyme inhibitory domain comprises one or more modifications that modulate basal prevention, attenuation, or inhibition compared to an otherwise identical enzyme inhibitory domain lacking one or more modifications. In some embodiments, the one or more modifications decrease basal prevention, attenuation, or inhibition compared to an otherwise identical enzyme inhibitory domain lacking one or more modifications. In some embodiments, the one or more modifications increase basal prevention, attenuation, or inhibition compared to an otherwise identical enzyme inhibitory domain lacking one or more modifications.

[0317] Activation and costimulatory domains In some embodiments, the cells disclosed herein can further comprise at least one tumor-targeting chimeric receptor or T cell receptor comprising an activation intracellular domain or a costimulatory intracellular domain. In some embodiments, the cells comprise at least one inhibitory chimeric receptor and at least one tumor-targeting chimeric receptor. The cells can comprise at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten or more tumor-targeting CARs, and at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten or more inhibitory chimeric receptors.

[0318] In some embodiments, the activation signaling domain is a CD3-zeta protein containing three immunoreceptor tyrosine-based activation motifs (ITAMs). Other examples of activation signaling domains include CD28, 4-1BB, and OX40. In some embodiments, a cell receptor contains two or more activation signaling domains, each referred to as a costimulatory domain.

[0319] In some embodiments, the tumor-targeting chimeric receptor is a chimeric antigen receptor (CAR) or an engineered T cell receptor. In some embodiments, the CAR binds one or more proteins expressed on the surface of tumor cells.

[0320] In some embodiments, the tumor-targeting chimeric receptor can activate the cell before the protein binds to the chimeric inhibitory receptor.

[0321] Transmembrane domain Inhibitory chimeric receptors may contain a transmembrane domain that links the protein binding domain to the intracellular domain. Different transmembrane domains result in different receptor stabilities. Suitable transmembrane domains include, but are not limited to, CD8, CD28, CD3 zeta, CD4, 4-IBB, OX40, ICOS, 2B4, CD25, CD7, LAX, LAT, LAIR1, PECAM-1, LIR, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0322] In some embodiments, the transmembrane domain is derived from a protein selected from the group consisting of CD8, CD28, CD3 zeta, CD4, 4-IBB, OX40, ICOS, 2B4, CD25, CD7, LAX, LAT, LAIR1, PECAM-1, LIR1, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM. In some embodiments, the transmembrane domain of the cellular receptor is a PECAM-1 transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is an LIR1 transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is an IRTA2 transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is an IRTA4 transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is an NKIR transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is an IL1RAP transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is a PTPRO transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is a PTPRZ1 transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is a TLT1 transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is an SLAMF1 transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is an SLAMF5 transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is a PCDHGC3 transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is a LIFR transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is an ERMAP transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is an IL1RAPL2 transmembrane domain.In some embodiments, the transmembrane domain of the cellular receptor is a CDH5 transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is an MPZL1 transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is an MPZ transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is an FCGR2B transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is a SIGLEC-6 transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is an MPIG6B transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is a VSIG4 transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is a SIGLEC-12 transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is an LIR8 transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is an IRTA1 transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is a KIR2DL4 transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is a KIR2DL5 transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is a SIGLEC-7 transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is a FCRH3 transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is a PCDHGC5 transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is a CDH11 transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is an IMPG2 transmembrane domain. In some embodiments, the transmembrane domain of the cellular receptor is a DSCAM transmembrane domain.

[0323] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from CD28.

[0324] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to FWVLVVVGGVLACYSLLVTVAFIIFWV (SEQ ID NO: 23). In some embodiments, the transmembrane domain comprises the amino acid sequence of FWVLVVVGGVLACYSLLVTVAFIIFWV (SEQ ID NO: 23).

[0325] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from PECAM-1.

[0326] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to GLIAVVIIGVIIALLIIAA (SEQ ID NO: 24). In some embodiments, the transmembrane domain comprises the amino acid sequence of GLIAVVIIGVIIALLIIAA (SEQ ID NO: 24).

[0327] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from LIR1.

[0328] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VIGILVAVILLLLLLLLLFLI (SEQ ID NO: 25). In some embodiments, the transmembrane domain comprises the amino acid sequence of VIGILVAVILLLLLLLLLFLI (SEQ ID NO: 25).

[0329] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from IRTA2.

[0330] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VAGGLLSIAGLAAGALLLYCW (SEQ ID NO: 26). In some embodiments, the transmembrane domain comprises the amino acid sequence of VAGGLLSIAGLAAGALLLYCW (SEQ ID NO: 26).

[0331] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from IRTA4.

[0332] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LWGLFGVLGFTGVALLLYALF (SEQ ID NO: 27). In some embodiments, the transmembrane domain comprises the amino acid sequence of LWGLFGVLGFTGVALLLYALF (SEQ ID NO: 27).

[0333] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from an NKIR.

[0334] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VLLPLIFTILLLLLVAASLLA (SEQ ID NO: 28). In some embodiments, the transmembrane domain comprises the amino acid sequence of VLLPLIFTILLLLLVAASLLA (SEQ ID NO: 28).

[0335] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from IL1RAP.

[0336] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VLLVVILIVVYHVYWLEMVLF (SEQ ID NO: 29). In some embodiments, the transmembrane domain comprises the amino acid sequence of VLLVVILIVVYHVYWLEMVLF (SEQ ID NO: 29).

[0337] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from PTPRO.

[0338] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to ISVLAILSTLLIGLLLVTLII (SEQ ID NO: 30). In some embodiments, the transmembrane domain comprises the amino acid sequence of ISVLAILSTLLIGLLLVTLII (SEQ ID NO: 30).

[0339] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, ie, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from PTPRZ1.

[0340] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to AVIPLVIVSALTFICLVVLVGILIYW (SEQ ID NO: 31). In some embodiments, the transmembrane domain comprises the amino acid sequence of AVIPLVIVSALTFICLVVLVGILIYW (SEQ ID NO: 31).

[0341] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from TLT1.

[0342] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LIWGAVLLVGLLVAAVVLFAV (SEQ ID NO: 32). In some embodiments, the transmembrane domain comprises the amino acid sequence of LIWGAVLLVGLLVAAVVLFAV (SEQ ID NO: 32).

[0343] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, ie, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from SLAMF1.

[0344] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to WAVYAGLLGGVIMILIMVVIL (SEQ ID NO: 33). In some embodiments, the transmembrane domain comprises the amino acid sequence of WAVYAGLLGGVIMILIMVVIL (SEQ ID NO: 33).

[0345] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, ie, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from SLAMF5.

[0346] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LLSVLAMFFLLVLILSSVFLF (SEQ ID NO: 34). In some embodiments, the transmembrane domain comprises the amino acid sequence of LLSVLAMFFLLVLILSSVFLF (SEQ ID NO: 34).

[0347] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from PCDHGC3.

[0348] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LLLSLILVSVGFVVTVFGVII (SEQ ID NO: 139). In some embodiments, the transmembrane domain comprises the amino acid sequence of LLLSLILVSVGFVVTVFGVII (SEQ ID NO: 139).

[0349] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from LIFR.

[0350] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VGLIIAILIPVAVAVIVGVVTSILC (SEQ ID NO: 140). In some embodiments, the transmembrane domain comprises the amino acid sequence of VGLIIAILIPVAVAVIVGVVTSILC (SEQ ID NO: 140).

[0351] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from an ERMAP.

[0352] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VALAVILPVLVLLIMVCLCLI (SEQ ID NO: 141). In some embodiments, the transmembrane domain comprises the amino acid sequence of VALAVILPVLVLLIMVCLCLI (SEQ ID NO: 141).

[0353] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from IL1RAPL2.

[0354] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to IELAGGLGAIFLLLVLLVVIY (SEQ ID NO: 142). In some embodiments, the transmembrane domain comprises the amino acid sequence of IELAGGLGAIFLLLVLLVVIY (SEQ ID NO: 142).

[0355] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from CDH5.

[0356] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to AVVAILLCILTITVITLLIFL (SEQ ID NO: 143). In some embodiments, the transmembrane domain comprises the amino acid sequence of AVVAILLCILTITVITLLIFL (SEQ ID NO: 143).

[0357] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, ie, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from MPZL1.

[0358] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to FPVWVVVGIVTAVVLGLTLLI (SEQ ID NO: 144). In some embodiments, the transmembrane domain comprises the amino acid sequence of FPVWVVVGIVTAVVLGLTLLI (SEQ ID NO: 144).

[0359] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from MPZ.

[0360] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to YGVVLGAVIGGVLGVVLLLLLLFYVV (SEQ ID NO: 145). In some embodiments, the transmembrane domain comprises the amino acid sequence of YGVVLGAVIGGVLGVVLLLLLLFYVV (SEQ ID NO: 145).

[0361] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, ie, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from FCGR2B.

[0362] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SSSPMGIIVAVVTGIAVAAIVAA (SEQ ID NO: 146). In some embodiments, the transmembrane domain comprises the amino acid sequence of SSSPMGIIVAVVTGIAVAAIVAA (SEQ ID NO: 146).

[0363] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, ie, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from SIGLEC-6.

[0364] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LGAVWGASITTLVFLCVCFIF (SEQ ID NO: 147). In some embodiments, the transmembrane domain comprises the amino acid sequence of LGAVWGASITTLVFLCVCFIF (SEQ ID NO: 147).

[0365] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from MPIG6B.

[0366] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LLIPLLGAGLVLGLGALGLVW (SEQ ID NO: 148). In some embodiments, the transmembrane domain comprises the amino acid sequence of LLIPLLGAGLVLGLGALGLVW (SEQ ID NO: 148).

[0367] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from VSIG4.

[0368] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VFAIILIISLCCMVVFTMAYI (SEQ ID NO: 149). In some embodiments, the transmembrane domain comprises the amino acid sequence of VFAIILIISLCCMVVFTMAYI (SEQ ID NO: 149).

[0369] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from SIGLEC-12.

[0370] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to FGGAGATALVFLYFCIIFVVV (SEQ ID NO: 150). In some embodiments, the transmembrane domain comprises the amino acid sequence of FGGAGATALVFLYFCIIFVVV (SEQ ID NO: 150).

[0371] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from LIR8.

[0372] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VVTGVSVAFVLLLFLLLFLLL (SEQ ID NO: 151). In some embodiments, the transmembrane domain comprises the amino acid sequence of VVTGVSVAFVLLLFLLLFLLL (SEQ ID NO: 151).

[0373] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from IRTA1.

[0374] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VAAGATGGLLSALLLAVALLF (SEQ ID NO: 152). In some embodiments, the transmembrane domain comprises the amino acid sequence of VAAGATGGLLSALLLAVALLF (SEQ ID NO: 152).

[0375] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from KIR2DL4.

[0376] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to AVIRYSVAIILFTILPFFLLH (SEQ ID NO: 153). In some embodiments, the transmembrane domain comprises the amino acid sequence of AVIRYSVAIILFTILPFFLLH (SEQ ID NO: 153).

[0377] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from KIR2DL5.

[0378] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LHILIGTSVAIILFIILFFFL (SEQ ID NO: 154). In some embodiments, the transmembrane domain comprises the amino acid sequence of LHILIGTSVAIILFIILFFFL (SEQ ID NO: 154).

[0379] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, ie, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from SIGLEC-7.

[0380] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to GAVGGAGATALVFLSFCVIFIVV (SEQ ID NO: 155). In some embodiments, the transmembrane domain comprises the amino acid sequence of GAVGGAGATALVFLSFCVIFIVV (SEQ ID NO: 155).

[0381] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, ie, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from FCRH3.

[0382] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to AAGITGLVLSILVLAAAAALL (SEQ ID NO: 156). In some embodiments, the transmembrane domain comprises the amino acid sequence of AAGITGLVLSILVLAAAAALL (SEQ ID NO: 156).

[0383] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from PCDHGC5.

[0384] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LIVALATVSLLSLVTFTFLSA (SEQ ID NO: 157). In some embodiments, the transmembrane domain comprises the amino acid sequence of LIVALATVSLLSLVTFTFLSA (SEQ ID NO: 157).

[0385] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, ie, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from CDH11.

[0386] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to GALIAILACIVILLVIVVLFVTL (SEQ ID NO: 158). In some embodiments, the transmembrane domain comprises the amino acid sequence of GALIAILACIVILLVIVVLFVTL (SEQ ID NO: 158).

[0387] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from IMPG2.

[0388] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to VIIGITIASVVGLLVIFSAII (SEQ ID NO: 159). In some embodiments, the transmembrane domain comprises the amino acid sequence of VIIGITIASVVGLLVIFSAII (SEQ ID NO: 159).

[0389] In some embodiments, the transmembrane domain and the intracellular signaling domain are derived from the same protein, hi some embodiments, the transmembrane domain is derived from a first protein and the intracellular signaling domain is derived from a second protein that is different from the first protein, wherein the chimeric inhibitory receptor comprises a transmembrane domain derived from DSCAM.

[0390] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to LVTISCILVGVLLLFVLLLVV (SEQ ID NO: 160). In some embodiments, the transmembrane domain comprises the amino acid sequence of LVTISCILVGVLLLFVLLLVV (SEQ ID NO: 160).

[0391] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 24. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 25. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 26. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 27. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO:28.In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 29. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO:30. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 31. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 32. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO:33.In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 34. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 139. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 140. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 141. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO:142.In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 143. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 144. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 145. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 146. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO:147.In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 148. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 149. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 150. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 151. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO:152.In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 153. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 154. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 155. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 156. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 157. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 158. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 159. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO:160.

[0392] Exemplary transmembrane domain protein sequences are shown in Table 3. Exemplary transmembrane domain nucleotide sequences are shown in Table 4.

[0393] (Table 3) TIFF2025526383000012.tif170157

[0394] (Table 4) TIFF2025526383000013.tif226157TIFF2025526383000014.tif64157

[0395] In some embodiments, the transmembrane domain is physically linked to the extracellular protein binding domain. In some embodiments, the intracellular signaling domain is physically linked to the transmembrane domain. In some embodiments, the transmembrane domain is physically linked to the extracellular protein binding domain and the intracellular signaling domain is physically linked to the transmembrane domain.

[0396] In some embodiments, the one or more intracellular signaling domains are two intracellular signaling domains.

[0397] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain and a second intracellular signaling domain, ie, a first intracellular signaling domain derived from PECAM-1 and a second intracellular signaling domain derived from a protein selected from the group consisting of CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0398] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from CD72 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0399] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from IRTA2 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0400] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from IRTA4 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0401] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from an NKIR and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0402] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from IL1RAP and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0403] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from PTPRO and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0404] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from PTPRZ1 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0405] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from TLT1 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0406] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from SLAMF1 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0407] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from SLAMF5 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0408] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from PCDHGC3 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0409] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from LIFR and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0410] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from ERMAP and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0411] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from IL1RAPL2 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0412] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from CDH5 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0413] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from MPZL1 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0414] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from MPZ and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0415] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from FCGR2B and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0416] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from SIGLEC-6 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0417] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from MPIG6B and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0418] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from VSIG4 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0419] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from SIGLEC-12 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0420] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from LIR8 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0421] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from IRTA1 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM.

[0422] In some embodiments, the chimeric inhibitory receptor comprises a first intracellular signaling domain derived from KIR2DL4 and a second intracellular signaling domain derived from a protein selected from the group consisting of PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG...

Claims

1. - extracellular protein binding domains, a transmembrane domain operably linked to said extracellular protein binding domain, and - one or more intracellular signaling domains operably linked to said transmembrane domain A chimeric inhibitory receptor comprising: the one or more intracellular signaling domains are each derived from a protein selected from the group consisting of MPZL1, IRTA1, LIR8, PECAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL1RAPL2, CDH5, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM; and at least one of the one or more intracellular signaling domains is capable of preventing, attenuating, or inhibiting activation of a tumor-targeting chimeric receptor expressed on an immunomodulatory cell; The chimeric inhibitory receptor.

2. a. the transmembrane domain is derived from the same protein as one of the one or more intracellular signaling domains, and optionally the transmembrane domain further comprises at least a portion of the extracellular domain of the same protein; or b. the transmembrane domain is derived from a first protein and the one or more intracellular signaling domains are derived from a protein different from the first protein; The chimeric inhibitory receptor of claim 1.

3. a. one of the one or more intracellular signaling domains is derived from PECAM-1, and optionally, one of the one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence b. one of the one or more intracellular signaling domains is derived from CD72, and optionally, one of the one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence c. one of the one or more intracellular signaling domains is derived from IRTA2, and optionally, one of the one or more intracellular signaling domains is: and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence d. one of the one or more intracellular signaling domains is derived from IRTA4, and optionally, one of the one or more intracellular signaling domains is and optionally the intracellular signaling domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence e. one of said one or more intracellular signaling domains is derived from an NKIR, and optionally, one of said one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence f. one of the one or more intracellular signaling domains is derived from IL1RAP, and optionally, one of the one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence g. one of the one or more intracellular signaling domains is derived from PTPRO, and optionally, one of the one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence h. one of the one or more intracellular signaling domains is derived from PTPRZ1, and optionally, one of the one or more intracellular signaling domains is: and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence i. one of the one or more intracellular signaling domains is derived from TLT1, and optionally, one of the one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence j. one of the one or more intracellular signaling domains is derived from SLAMF1, and optionally, one of the one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence k. one of the one or more intracellular signaling domains is derived from SLAMF5, and optionally, one of the one or more intracellular signaling domains is: and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence l. one of the one or more intracellular signaling domains is derived from PCDHGC3, and optionally, one of the one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence m. one of said one or more intracellular signaling domains is derived from LIFR, and optionally, one of said one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence n. one of said one or more intracellular signaling domains is derived from an ERMAP, and optionally, one of said one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence o. one of the one or more intracellular signaling domains is derived from IL1RAPL2, and optionally, one of the one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence p. one of the one or more intracellular signaling domains is derived from CDH5, and optionally, one of the one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence q. one of the one or more intracellular signaling domains is derived from MPZL1, and optionally, one of the one or more intracellular signaling domains is: and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence r. one of said one or more intracellular signaling domains is derived from MPZ, and optionally, one of said one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence s. one of the one or more intracellular signaling domains is derived from FCGR2B, and optionally, one of the one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence t. one of the one or more intracellular signaling domains is derived from SIGLEC-6, and optionally, one of the one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence u. one of the one or more intracellular signaling domains is derived from MPIG6B, and optionally, one of the one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence v. one of said one or more intracellular signaling domains is derived from VSIG4, and optionally, one of said one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence w. one of the one or more intracellular signaling domains is derived from SIGLEC-12, and optionally, one of the one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence x. one of said one or more intracellular signaling domains is derived from LIR8, and optionally, one of said one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence y. one of the one or more intracellular signaling domains is derived from IRTA1, and optionally, one of the one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence z. one of said one or more intracellular signaling domains is derived from KIR2DL4, and optionally, one of said one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence aa. one of the one or more intracellular signaling domains is derived from KIR2DL5, and optionally, one of the one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence bb. one of the one or more intracellular signaling domains is derived from SIGLEC-7, and optionally, one of the one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence cc. one of the one or more intracellular signaling domains is derived from FCRH3, and optionally, one of the one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence dd. one of the one or more intracellular signaling domains is derived from PCDHGC5, and optionally, one of the one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence one of the one or more intracellular signaling domains is derived from CDH11, and optionally, one of the one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence ff. one of the one or more intracellular signaling domains is derived from IMPG2, and optionally, one of the one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence wherein one of the one or more intracellular signaling domains is derived from DSCAM, and optionally, one of the one or more intracellular signaling domains is and optionally, one of the one or more intracellular signaling domains comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence A chimeric inhibitory receptor according to claim 1 or 2.

4. - extracellular protein binding domains, a transmembrane domain operably linked to said extracellular protein binding domain, and - one or more intracellular signaling domains operably linked to said transmembrane domain A chimeric inhibitory receptor comprising: at least one of the one or more intracellular signaling domains (i) at least one immunoreceptor tyrosine-dependent switch motif (ITSM), or (ii) at least one ITIM and at least one phosphatase and at least one of the one or more intracellular signaling domains is capable of preventing, attenuating, or inhibiting activation of a tumor-targeting chimeric receptor expressed on an immunomodulatory cell; The chimeric inhibitory receptor.

5. the chimeric inhibitory receptor comprises at least one ITIM and at least one phosphatase, optionally the phosphatase is a protein tyrosine phosphatase (PTP), optionally the one or more intracellular signaling domains are each derived from a protein selected from the group consisting of PTPRO and PTPRZ1, and optionally a. one of the one or more intracellular signaling domains is derived from a PTPRO, and optionally, the intracellular signaling domain comprises: and optionally the intracellular signaling domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or b. one of the one or more intracellular signaling domains is derived from PTPRZ1, and optionally, the intracellular signaling domain is: and optionally the intracellular signaling domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence The chimeric inhibitory receptor of claim 4.

6. the chimeric inhibitory receptor comprises at least one ITSM, and optionally, the one or more intracellular signaling domains are each derived from a protein selected from the group consisting of SLAMF1 and SLAMF5, and optionally: a. one of the one or more intracellular signaling domains is derived from SLAMF1, and optionally, the intracellular signaling domain is: and optionally the intracellular signaling domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or b. one of the one or more intracellular signaling domains is derived from SLAMF5, and optionally, the intracellular signaling domain is: and optionally the intracellular signaling domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence The chimeric inhibitory receptor of claim 4.

7. The transmembrane domain is selected from the group consisting of CD8, CD28, CD3ζ, CD4, 4-IBB, OX40, ICOS, 2B4, CD25, CD7, LAX, LAT, LIR1, PCAM-1, CD72, IRTA2, IRTA4, NKIR, IL1RAP, PTPRO, PTPRZ1, TLT1, SLAMF1, SLAMF5, PCDHGC3, LIFR, ERMAP, IL 1RAPL2, CDH5, MPZL1, MPZ, FCGR2B, SIGLEC-6, MPIG6B, VSIG4, SIGLEC-12, LIR8, IRTA1, KIR2DL4, KIR2DL5, SIGLEC-7, FCRH3, PCDHGC5, CDH11, IMPG2, and DSCAM, and optionally a. the chimeric inhibitory receptor comprises a transmembrane domain derived from PECAM-1, and optionally, the transmembrane domain is and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or b. the chimeric inhibitory receptor comprises a transmembrane domain derived from LIR1, and optionally, the transmembrane domain comprises: and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or c. the chimeric inhibitory receptor comprises a transmembrane domain derived from IRTA2, optionally the transmembrane domain comprising: and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or d. the chimeric inhibitory receptor comprises a transmembrane domain derived from IRTA4, optionally the transmembrane domain comprising: and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or e. the chimeric inhibitory receptor comprises a transmembrane domain derived from an NKIR, optionally the transmembrane domain comprising: and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or f. the chimeric inhibitory receptor comprises a transmembrane domain derived from IL1RAP, optionally wherein the transmembrane domain is and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or g. the chimeric inhibitory receptor comprises a transmembrane domain derived from a PTPRO, optionally wherein the transmembrane domain is and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or h. the chimeric inhibitory receptor comprises a transmembrane domain derived from PTPRZ1, optionally wherein the transmembrane domain is: and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or i. the chimeric inhibitory receptor comprises a transmembrane domain derived from TLT1, optionally wherein the transmembrane domain comprises: and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or j. the chimeric inhibitory receptor comprises a transmembrane domain derived from SLAMF1, and optionally, the transmembrane domain comprises: and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or k. the chimeric inhibitory receptor comprises a transmembrane domain derived from SLAMF5, and optionally, the transmembrane domain is and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or l. the chimeric inhibitory receptor comprises a transmembrane domain derived from PCDHGC3, optionally the transmembrane domain comprising: and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or m. the chimeric inhibitory receptor comprises a transmembrane domain derived from LIFR, optionally wherein the transmembrane domain is and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or n. the chimeric inhibitory receptor comprises a transmembrane domain derived from ERMAP, and optionally, the transmembrane domain comprises: and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or o. the chimeric inhibitory receptor comprises a transmembrane domain derived from IL1RAPL2, optionally wherein the transmembrane domain comprises: and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or p. the chimeric inhibitory receptor comprises a transmembrane domain derived from CDH5, optionally the transmembrane domain comprising: and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or q. the chimeric inhibitory receptor comprises a transmembrane domain derived from MPZL1, and optionally, the transmembrane domain is and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or r. the chimeric inhibitory receptor comprises a transmembrane domain derived from MPZ, optionally wherein the transmembrane domain is and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or s. the chimeric inhibitory receptor comprises a transmembrane domain derived from FCGR2B, and optionally, the transmembrane domain comprises: and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or t. the chimeric inhibitory receptor comprises a transmembrane domain derived from SIGLEC-6, and optionally, the transmembrane domain comprises: and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or u. the chimeric inhibitory receptor comprises a transmembrane domain derived from MPIG6B, optionally the transmembrane domain comprising: and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or v. the chimeric inhibitory receptor comprises a transmembrane domain derived from VSIG4, optionally wherein the transmembrane domain is and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or w. the chimeric inhibitory receptor comprises a transmembrane domain derived from SIGLEC-12, and optionally, the transmembrane domain comprises: and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or x. the chimeric inhibitory receptor comprises a transmembrane domain derived from LIR8, optionally wherein the transmembrane domain is and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or y. the chimeric inhibitory receptor comprises a transmembrane domain derived from IRTA1, optionally wherein the transmembrane domain is: and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or z. the chimeric inhibitory receptor comprises a transmembrane domain derived from KIR2DL4, optionally the transmembrane domain comprising: and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or aa. The chimeric inhibitory receptor comprises a transmembrane domain derived from KIR2DL5, and optionally, the transmembrane domain is and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or bb. the chimeric inhibitory receptor comprises a transmembrane domain derived from SIGLEC-7, and optionally, the transmembrane domain comprises: and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or cc. the chimeric inhibitory receptor comprises a transmembrane domain derived from FCRH3, and optionally, the transmembrane domain comprises: and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or dd. The chimeric inhibitory receptor comprises a transmembrane domain derived from PCDHGC5, and optionally, the transmembrane domain is and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or ee. the chimeric inhibitory receptor comprises a transmembrane domain derived from CDH11, and optionally, the transmembrane domain comprises: and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or ff. the chimeric inhibitory receptor comprises a transmembrane domain derived from IMPG2, and optionally, the transmembrane domain comprises: and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to or gg. The chimeric inhibitory receptor comprises a transmembrane domain derived from DSCAM, and optionally, the transmembrane domain comprises: and optionally the transmembrane domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to comprising the amino acid sequence A chimeric inhibitory receptor according to any one of claims 1 to 6.

8. (i) the protein is not expressed on the target tumor, and optionally the protein is expressed on a non-tumor cell, and optionally the protein is expressed on a non-tumor cell derived from a tissue selected from the group consisting of brain, neuronal tissue, endocrine glands, endothelium, bone, bone marrow, immune system, muscle, lung, liver, gallbladder, pancreas, gastrointestinal tract, kidney, urinary bladder, male reproductive organs, female reproductive organs, adipose, soft tissue, and skin; and / or (ii) the extracellular protein-binding domain comprises a ligand-binding domain, a receptor-binding domain, and / or an antigen-binding domain, optionally wherein the antigen-binding domain comprises an antibody, an antigen-binding fragment of an antibody, an F(ab) fragment, an F(ab') fragment, a single-chain variable fragment (scFv), or a single-domain antibody (sdAb), optionally wherein the antigen-binding domain comprises a single-chain variable fragment (scFv), optionally wherein the scFv comprises a heavy chain variable domain (VH) and a light chain variable domain (VL), optionally wherein the VH and VL are separated by a peptide linker, optionally wherein the peptide linker is and optionally the scFv comprises the structure VH-L-VL or VL-L-VH, wherein VH is the heavy chain variable domain, L is the peptide linker, and VL is the light chain variable domain. A chimeric inhibitory receptor according to any one of claims 1 to 7.

9. the chimeric inhibitory receptor a spacer region disposed between the extracellular protein binding domain and the transmembrane domain and operably linked, e.g., physically linked, to each of the extracellular protein binding domain and the transmembrane domain; further comprising Optionally, the spacer region is derived from a protein selected from the group consisting of CD8α, CD4, CD7, CD28, IgG1, IgG4, FcγRIIIα, LNGFR, and PDGFR; Optionally, the spacer region comprises: comprising an amino acid sequence selected from the group consisting of: A chimeric inhibitory receptor according to any one of claims 1 to 8.

10. the chimeric inhibitory receptor an intracellular spacer region disposed between the transmembrane domain and one of the one or more intracellular signaling domains and operably linked, e.g., physically linked, to each of the transmembrane domain and one of the one or more intracellular signaling domains; The chimeric inhibitory receptor of any one of claims 1 to 9, further comprising:

11. 11. The chimeric inhibitory receptor of any one of claims 1 to 10, wherein the inhibitory chimeric receptor further comprises an enzyme inhibitory domain, optionally capable of preventing, attenuating, or inhibiting activation of a tumor-targeting chimeric receptor when expressed on an immunomodulatory cell compared to an otherwise identical chimeric inhibitory receptor lacking the enzyme inhibitory domain, and optionally wherein the enzyme inhibitory domain comprises an enzyme catalytic domain, optionally wherein the enzyme catalytic domain is derived from an enzyme selected from the group consisting of CSK, SHP-1, PTEN, CD45, CD148, PTP-MEG1, PTP-PEST, c-CBL, CBL-b, PTPN22, LAR, PTPH1, SHIP-1, and RasGAP.

12. The chimeric inhibitory receptor of any one of claims 1 to 11, wherein the tumor-targeting chimeric receptor is a chimeric antigen receptor (CAR) or an engineered T-cell receptor (TCR).

13. 13. The chimeric inhibitory receptor of any one of claims 1 to 12, wherein the immunoregulatory cell is selected from the group consisting of T cells, CD8+ T cells, CD4+ T cells, gamma-delta T cells, cytotoxic T lymphocytes (CTLs), regulatory T cells, virus-specific T cells, natural killer T (NKT) cells, natural killer (NK) cells, B cells, tumor-infiltrating lymphocytes (TILs), innate lymphocytes, mast cells, eosinophils, basophils, neutrophils, myeloid cells, macrophages, monocytes, dendritic cells, ESC-derived cells, and iPSC-derived cells, and optionally the immunoregulatory cell is a natural killer (NK) cell.

14. A chimeric inhibitory receptor according to any one of claims 1 to 13, and a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, or a combination thereof A composition comprising:

15. An engineered nucleic acid encoding the chimeric inhibitory receptor of any one of claims 1 to 13.

16. 16. An expression vector comprising the engineered nucleic acid of claim 15.

17. 17. A composition comprising the engineered nucleic acid of claim 15 or the expression vector of claim 16, and a pharmaceutically acceptable carrier.

18. A producer cell or isolated immunomodulatory cell comprising a chimeric inhibitory receptor according to any one of claims 1 to 13, an engineered nucleic acid according to claim 15, or an expression vector according to claim 16.

19. 19. The isolated cell of claim 18, and a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, or a combination thereof A composition comprising:

20. 1. A method of preventing, attenuating, or inhibiting a cell-mediated immune response induced by a tumor-targeting chimeric receptor expressed on the surface of an immunomodulatory cell, comprising: engineering said immunomodulatory cells to express the chimeric inhibitory receptor of any one of claims 1 to 13 on their surface; The method, wherein the intracellular signaling domain prevents, attenuates, or inhibits activation of the tumor-targeting chimeric receptor upon binding of a cognate antigen to the chimeric inhibitory receptor.

21. 1. A method of preventing, attenuating, or inhibiting activation of a tumor-targeting chimeric receptor expressed on the surface of an immunomodulatory cell, comprising: contacting the isolated cell of claim 18 or the composition of claim 19 with a cognate antigen of said chimeric inhibitory receptor under conditions suitable for said chimeric inhibitory receptor to bind said cognate antigen; The method, wherein the intracellular signaling domain prevents, attenuates, or inhibits activation of the tumor-targeted chimeric receptor upon binding of the antigen to the chimeric inhibitory receptor.

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