GPR25 agonization for cancer therapy

Abstract

Provided herein are methods of modulating an immune response to a tumor or cancer cell in a patient, treating cancer or a tumor in a cancer patient, eliciting an anti-cancer or tumor response in a patient, or treating or ameliorating an infection in a subject in need thereof. The methods comprise modulating expression or activity of G Protein-Coupled Receptor 25 (GPR25) in a T cell in the patient.

Description

[0001]Atty. Dkt. No.: 116639-2710 GPR25 AGONIZATION FOR CANCER THERAPY CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 610,969, filed December 15, 2023, the contents of which is incorporated herein by reference in their entireties. FIELD OF THE DISCLOSURE The present disclosure generally relates to the treatment of cancer through agonizing G Protein-Coupled Receptor 25 (GPR25). BACKGROUND OF THE DISCLOSURE The following description of the background of the present technology is provided simply as an aid in understanding the present technology and is not admitted to describe or being prior art to the present technology. G Protein-Coupled Receptor 25 (GPR25) is expressed in Tissue-resident memory CD8+T (TRM) cells, which are a distinct population of memory T cells that primarily resides within tissues and respond immediately against pathogens invading barrier tissues, thus representing the first-line of defense. GPRs are the largest superfamily of transmembrane receptors in the genome, they interact with a large number of extracellular ligands and transmit intracellular signals by activating heterotrimeric guanine nucleotide-binding proteins. SUMMARY OF THE DISCLOSURE To address the above identified limitations in the art, this disclosure provides methods of treating cancer, eliciting an anti-tumor response in a subject in need thereof, or treating or ameliorating an infection in a subject in need thereof, the methods comprising, or consisting essentially of, or consisting of modulating the expression of G Protein-Coupled Receptor 25 (GPR25) in the patient. In alternative aspects, the disclosure provides methods of administering an agent capable of modulating the expression or activity of GPR25 in a T cell in the patient. In yet another aspect, the disclosure provides method of promoting the development Atty. Dkt. No.: 116639-2710 of TRM cells in a subject. In yet another aspect, the disclosure provides a method of promoting development of stem-like TRM cells in a subject. In one aspect, the methods comprise, or consist essentially of, or yet further consist of administering to the patient an agent that comprises, consists of, or consists essentially of a small molecule or a protein, for example TGF-β. In some aspects, the T cell is selected from the group of: an activated T cell; a tissue-resident memory (TRM) cell; and a stem T cell. In some aspects, the activated T cell is specific for a tumor- specific antigen or a tumor-associated antigen expressed by the cancer or tumor cell, wherein the tumor-associated antigen is optionally overexpressed by the tumor cell. In some aspects of the method, the modulation comprises, consists of, or consists essentially of activating the T cell by agonizing the expression or activity of GPR25 in the T cell. In further aspects, the agent comprises, consists of, or consists essentially of a bispecific agent that binds to GPR25 and binds to a second receptor expressed by the T cell. In some aspects, the second receptor is selected from the group CXCR5, CXCR6, CD8, CD103, CD49A, CD69, CD3, CD28, CD8 or PD1. In some aspects, the second receptor is CXCR5. In yet another aspect, the bispecific agent comprises, consists of, or consists essentially of a bispecific antibody that binds to GPR25 and the second receptor expressed by the T cell, e.g., selected from the group CXCR5, CXCR6, CD8, CD103, CD49A, CD69, CD3, CD28, CD8 or PD1. In yet another aspect, the agent that binds to GPR25 is or, comprises, consists of, or consists essentially of an agonistic antibody. In yet another aspect, the agent comprises, consists of, or consists essentially of a bispecific antibody that binds to GPR25 and the second molecule expressed by the T cell. In yet another aspect, the agent binds to GPR25 and binds to a tumor antigen expressed by a tumor cell. In some aspects, the tumor antigen is overexpressed by the tumor cell. In some aspects, the tumor antigen comprises, consists of, or consists essentially of a tumor- associated antigen or a tumor-specific antigen. In some aspects, the tumor antigen comprises, consists of, or consists essentially of a tumor-associated antigen or a tumor-specific antigen. In some aspects, the tumor-associated antigen is overexpressed by the tumor cell. In some aspects, the tumor antigen comprises, consists of, or consists essentially of a lung cancer antigen or a Atty. Dkt. No.: 116639-2710 lymphatic tissue antigen. In some aspects, the tumor antigen is selected from the group of MAGE-D4B, PSMA, HER2, HER3, EGFR, AFP, CEA, CA-125, MUC-1, ETA, MUC-1, BAGE, GAGE-1, MAGE-A1, NY-ESO-1, Gp100, Melan-A / MART-1, Prostate-specific antigen, Mammaglobin-A, Alpha-fetoprotein, HER-2 / neu, P53, K-ras, or TRP-2 / INT2 In some aspects, the cancer or tumor cell and / or the cancer or tumor is or is selected from the group of a tumor cell or tissue from a tumor cell or cancer of: the circulatory system; the respiratory tract; the gastrointestinal system the genitourinary tract; the liver; a bone; the nervous system; the reproductive system; the hematologic system; the oral cavity; skin and other tissues comprising connective and soft tissue, retroperitoneum and peritoneum, eye, intraocular melanoma, and adnexa, breast, head or / and neck, anal region, thyroid, parathyroid, adrenal gland and other endocrine glands and related structures, and lymph nodes, optionally wherein the cancer is a solid tumor or alternatively wherein the cancer is a liquid cancer, and further optionally wherein the cancer is a primary cancer or a metastasis and / or a cancer selected from a carcinoma, a sarcoma, a myeloma, a leukemia, or lymphoma, testis cancer, brain cancer, a metastasis or recurring cancer a non-small cell lung cancer (NSCLC) and / or head and neck squamous cell cancer (HNSCC). In some aspects, the cancer or tumor cell and / or the cancer or tumor comprises, consists of, or consists essentially of a cancer or tumor of a tissue or cell from the respiratory tract or lymph nodes. In some aspects, the cancer comprises, consist of, or consists essentially of a localized or metastatic cancer. In some aspects, the subject being treated is a mammal or animal, e.g., a human patient. In some aspects, the subject or patient has reduced expression of GPR25 compared to that of a healthy, non-diseased subject. In some aspects, the methods further comprise, consist of, or consist essentially of resecting the tumor or cancer prior to modulating the expression or activity of GPR25 in the T cell in the patient. In some aspects, the modulating expression or activity of GPR25 in a T cell is administered as a first-line, a second-line, a third-line, a fourth-line or fifth-line therapy. In some aspects, the methods further comprise, consist of, or consist essentially of administering an effective amount of a different anti-cancer agent to the patient. In some aspects, the treating Atty. Dkt. No.: 116639-2710 cancer or a tumor in a cancer patient comprises, consists of, or consists essentially of one or more of providing to the subject or patient one or more of: a reduction in tumor burden, longer overall survival or prolonged time to tumor progression. In yet another aspect, provided herein is a method for screening for a GPR25 anticancer therapy comprising, consisting of, or consisting essentially of contacting a first sample of T cells with an amount of the test agent that binds to GPR25 and a second agent that binds a tumor antigen, and assaying for increased expression of GPR25 in the T cell. In some aspects, increased expression of GPR25 in the T cell is an indication that the agent is a GPR25 anticancer therapy. In yet another aspect, provided herein is a method of modulating GPR25 in a subject, the method comprising, consisting of, or consisting essentially of administering a bispecific antibody that targets and binds to GPR25 and a second receptor expressed by a T cell. In some aspects, the receptor is selected from the group of: CXCR5, CXCR6, CD8, CD103, CD49A, CD69, CD3, or PD1. In some aspects, the T cell is a stem T cell. In some aspects, the subject or patient is a human patient. In yet another aspect, provided herein is a method of determining prognosis of a subject having cancer comprising, consisting of, or consisting essentially contacting T cells isolated from the subject with an antibody or agent that recognizes and binds to GPR25 to determine the frequency of T cells expressing GPR25, wherein a high density of GPR25 in T cells indicates a more positive prognosis or wherein a low density of GPR25 in T cells indicates a more negative prognosis. In some aspects, the more negative prognosis comprises, consists of, or consists essentially of a decreased probability in survival, and wherein the more positive prognosis comprises, consists of, or consists essentially of an increased probability in survival. After determination, the method can further comprise administering to the subject an effective amount of a therapy that is consistent with the prognosis. In yet another aspect, provided herein is a method of determining the responsiveness of a subject to cancer therapy that modulates GPR25, the method comprising, consisting of, or consisting essentially contacting T cells isolated from the subject with an antibody or agent that recognizes and binds to GPR25 to determine the frequency of GPR25 Atty. Dkt. No.: 116639-2710 expressing T cells in the subject, wherein a high frequency of GPR25 T cells indicates an increased likelihood of responsiveness to a cancer therapy. In some aspects, the cancer therapy comprises, consists of, or consists essentially of an agent that modulates the expression and / or activity of GPR25 in the subject. In some aspects, the density of GPR25 in T cells in the subject is compared to a healthy, non-diseased subject. In some aspects, the methods further comprise, consist of, or consist essentially of administering a cancer therapy that modulates GPR25 to the subject. In some aspects, the cancer therapy comprises, consists of, or consists essentially of an agent that binds to GPR25. In some aspects, the agent comprises, consists of, or consists essentially of an agonistic antibody targeting GPR25. In some aspects, the sample is contacted with an agent. In some aspects, the agent is detectably labeled. In some aspects, the detectable label or tag comprises, consists of, or consists essentially of a radioisotope, a metal, horseradish peroxidase, alkaline phosphatase, avidin or biotin. In some aspects, the agent comprises, consists of, or consists essentially of a polypeptide that binds to an expression product encoded by GPR25, or a polynucleotide that hybridizes to a nucleic acid sequence encoding all or a portion of GPR25. In some aspects, the polypeptide comprises, consists of, or consists essentially an antibody, an antigen binding fragment thereof, or a receptor that binds to the GPR25. In some aspects, the antibody comprises, consists of, or consists essentially of an IgG, IgA, IgM, IgE or IgD, or a subclass thereof. In some aspects, the IgG comprises, consists of, or consists essentially of IgG1, IgG2, IgG3 or IgG4. In some aspects, the antigen binding fragment comprises, consists of, or consists essentially of a Fab, Fab’, F(ab’)2, Fv, Fd, single-chain Fvs (scFv), disulfide-linked Fvs (sdFv) or VL or VH. In some aspects, the agent is contacted with the sample in conditions favoring binding of the agent to GPR25. In some aspects of the methods disclosed herein, the agent is contacted with the sample in conditions favoring binding of the agent to GPR25. In some aspects, the methods comprise, consist of, or consist essentially of detection by immunohistochemistry (IHC), in-situ hybridization (ISH), ELISA, immunoprecipitation, immunofluorescence, chemiluminescence, Atty. Dkt. No.: 116639-2710 radioactivity, X-ray, nucleic acid hybridization, protein-protein interaction, immunoprecipitation, flow cytometry, Western blotting, polymerase chain reaction, DNA transcription, Northern blotting and / or Southern blotting. In some aspects, the sample comprises, consists of, or consists essentially of cells, tissue, an organ biopsy, an epithelial tissue, a lung, respiratory or airway tissue or organ, a circulatory tissue or organ, a skin tissue, bone tissue, muscle tissue, head, neck, brain, skin, bone and / or blood sample. In yet another aspect, provide herein is a method of treating cancer in a subject, comprising, consisting of, or consisting essentially of administering a T cell having increased expression of GPR25 to the subject, optionally as compared to the T cells of a subject having the cancer. In some aspects, the cancer or tumor cell and / or the cancer or tumor comprises, consists of, or consists essentially of a cancer or tumor of a tissue or cell from the respiratory tract or lymph nodes. In some aspects, the cancer or tumor cell and / or the cancer or tumor comprises, consists of, or consists essentially of a cancer or tumor of a tissue or cell from the respiratory tract or lymph nodes a cancer or tumor of a tissue or cell from the respiratory tract. In some aspects, the cancer or tumor cell and / or the cancer or tumor comprises, consists of, or consists essentially of a metastatic cancer. In some aspects, the metastatic cancer comprises, consists of, or consists essentially of metastatic lung cancer. In some aspects, the patient is a human patient. In some aspects, the patient has reduced expression of GPR25 compared to that of a healthy, non-diseased subject. In some aspects, the T cell comprises, consists of, or consists essentially of an activated T cell; a tissue-resident memory (TRM) cell; a stem T cell. In some aspects, the activated T cell is specific for a tumor-specific antigen or a tumor-associated antigen expressed by the tumor cell, wherein the tumor-associated antigen is optionally overexpressed by the tumor cell. In some aspects, the T cell comprises, consists of, or consists essentially of a TRM cell. In yet another aspect, provided herein are methods of promoting the development of TRM cells and / or stem-like TRM cells in a subject. In some aspects, the methods comprise, consist of, or consist essentially of administering an agent that modulates expression of GPR25 to the subject. In some aspects, the TRM cells are in the lung tissue or liver tissue of the subject. In some aspects, the agent is administered to the lung tissue or liver tissue of the subject. In some Atty. Dkt. No.: 116639-2710 aspects, the agent comprises, consists of, or consists essentially of a small molecule or a protein selected from the group of: Transforming Growth Factor-β (TGF-β), Nuclear Factor of Activated T-cells (NFAT), or Suppressor of Mothers Against Decapentaplegic family member 1 (SMAD1), or equivalents thereof. BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1A – 1D: TGF-β induces expression of GPR25 in CD8+T cells. (FIG. 1A), Quantitative real-time PCR (qRT-PCR) analysis of GPR25 expression levels in naïve human CD8+T cells stimulated with anti-CD3 and anti-CD28 in the presence or absence of TGF-β for 24 and 48 hours. (FIG. 1B), UCSC genome browser tracks for genes in the extended GPR25 locus (50 kb), ATAC-seq tracks in the indicated CD8+T cell populations (top) and ENCODE chromatin immunoprecipitation sequencing tracks for NFATC1, NFATC3 and SMAD1 (bottom); C1, C2 and C3 cis-regulatory regions are shaded. (FIG. 1C), Gpr25 expression levels in naïve murine CD8+T (CD8+CD44loCD62Lhi) stimulated with anti-CD3 and anti-CD28 in the presence or absence of TGF-β at the indicated time points. (FIG. 1D), Gpr25 expression levels in CD8β+T cells (spleen), CD8β+CD69+and CD8β+CD69−T cells (liver), CD8α+CD8α+and CD8α+CD8β+T cells (siIEL) isolated from unmanipulated wild-type C57BL / 6J mice (>90 days old). Graphs in (FIG. 1A), and (FIG. 1D) depict mean ± S.E.M.; graphs in (FIG. 1A), and (FIG. 1D) depict mean ± S.D.; all data are representative of two independent experiments, with n = 5-11 in each experiment. Statistical significance for the comparisons was computed using two-tailed two unequal variance Student t test; *P < 0.05, **P < 0.01 and **** P < 0.0001. FIGS. 2A – 2E: Gpr25 promotes the development of liver TRMcells. (FIG. 2A), Illustration of the TRMmodel in which congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred at a 1:1 ratio into CD45.1 recipient mice before infection with LCMV-OVA (i.p.). (FIGS. 2B – 2C), Flow-cytometric analysis of CD8+T cells isolated from the spleen, liver, and small intestinal intraepithelial lymphocytes (siIEL) of recipient mice (n = 8) at 90 days post infection. (FIG. 2B), Representative contour plots and the frequencies of transferred Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells are shown. (FIG. 2C), Representative contour plots Atty. Dkt. No.: 116639-2710 and frequencies of transferred Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I CD8+T cells that express CD69 and CXCR6, CD69 and CD103 are shown. (FIG. 2D), Illustration of parabiosis experimental workflow. Congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred at a 1:1 ratio into CD45.1 (host) mice before infection with LCMV-OVA (i.p.). Thirty days post infection, anti-Gr1 were administrated as previous described25to eliminate circulating lymphocytes. Seven days after anti-Gr1 administration, CD8KO (recipient) mice were co-joined with CD45.1 mice (host) via parabiosis surgery. Mice were analyzed 30 days after the surgery. (FIG. 2E), Flow-cytometric analysis of CD8+T cells isolated from the liver of host mice and spleen of recipient mice at 30 days after parabiosis surgery. Representative contour plots and frequencies of transferred Gpr25+ / +(WT; CD45.1.2), Gpr25- / -(KO; CD45.2) OT-I CD8+T cells from the liver of host CD45.1 mice and spleen of recipient mice are shown. Bar graphs in (FIGS. 2B – 2C, FIG. 2E) depict mean, each symbol represents data from an individual mouse; all data from (FIGS. 2B – 2C) are representative of three independent experiments; data from (FIG. 2E) are pooled data from two independent experiments. Statistical significance for the comparisons was computed using two- tailed two unequal variance Student t test; *P < 0.05, **P < 0.01 and *** P < 0.001. FIGS. 3A – 3E: Gpr25 deficiency impairs early stages of TRMcell development. (FIG. 3A), Illustration of the TRM model in which congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred at a 1:1 ratio into CD45.1 recipient mice before infection with LCMV-OVA (i.p.). (FIGS. 3B – 3E), Flow- cytometric analysis of CD8+T cells isolated from the liver of recipient mice (n = 4) at 24 hours, 48 hours, days 5, 12 and 30 post infection. (FIG.3B), For the in vivo T cell proliferation assay, CTV-labeled OT-I cells were adoptively transferred into recipient mice before infection. Representative histogram and frequencies of proliferating OT-I cells are shown. (FIG. 3C), Representative contour plots and frequencies of transferred Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I CD8+T cells that express CD69 and KLRG1 are shown for the indicated time point post infection. (FIG. 3D), Representative contour plots and the frequencies of transferred Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells are shown. (FIG. 3E), Representative contour plots and frequencies of transferred Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I CD8+T cells that express CD69 and CXCR6 in the spleen and liver are shown; numbers adjacent to outlined areas indicate frequencies of cells co-expressing CD69 and CXCR6. Bar Atty. Dkt. No.: 116639-2710 graphs in (FIGS. 3B – 3E) depict mean, each symbol represents data from an individual mouse; all data from (FIGS. 3B – 3E) are representative of three independent experiments. Statistical significance for the comparisons was computed using two-tailed two unequal variance Student t test; *P < 0.05 and **P < 0.01. FIGS. 4A – 4K: Gpr25 promotes the development of secondary TRMcells. (FIG. 4A), (FIG. 4B), Congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred at a 1:1 ratio into CD45.1 recipient mice before infection with LCMV-OVA (i.p.). Single-cell RNA-seq was performed on Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I TRMcells (CD69+CD62L-KLRG1-) isolated from CD8+T cells in the liver of recipient mice (n = 8) at 30 days post infection. (FIG. 4A), Volcano plot shows false discovery rate (FDR) and fold change in expression levels of differentially expressed transcripts (False discovery rate (FDR) ≤ 0.05, fold change > 0.25) between Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I TRMcells; dashed lines depict the threshold used for fold change and FDR; full list of differentially expressed transcripts is provided in Table 1. (FIG. 4B), Gene- set enrichment analysis (GSEA) plot shows enrichment of the indicated gene signatures when comparing Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I TRMcells. False discovery rate (FDR) and normalized enrichment score (NES) were determined using fgsea package on R. (FIG. 4C), Quantitative real-time PCR (qRT-PCR) analysis of Tcf7 expression levels and (FIG. 4D) mean fluorescence intensity (MFI) of TCF1 in Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I TRMcells in the liver 30 days post infection. (FIG. 4E), Illustration of the secondary TRMmodel in which congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I TRM cells, generated as described in Fig. 3a, were isolated from liver and co-transferred at a 1:1 ratio into CD45.1 naïve recipient mice before infection with LCMV-OVA (i.p.). (FIGS. 4F – 4H), Flow- cytometric analysis of CD8+T cells isolated from the liver of recipient mice (n = 4) at 30 days post infection. (FIG. 4F), Representative contour plots and the frequencies of transferred Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I T cells in the liver are shown. (FIG. 4G) (FIG. 4H), Representative contour plots and frequencies of transferred Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I TRM cells in the liver that express CD69 and CXCR6 (FIG. 4G), CD69 and KLRG1 (FIG. 4H) are shown; numbers adjacent to outlined areas (FIG. 4G) indicate percentage of cells co-expressing CD69 and CXCR6. (FIG. 4I), GSEA plot shows positive enrichment of TGF-β response gene signatures, from the indicated source, in Gpr25+ / +(WT) OT-I when Atty. Dkt. No.: 116639-2710 compared to Gpr25- / -(KO) OT-I TRM cells. (FIG. 4J), Flow-cytometric analysis naïve murine CD8+T cells (CD8+CD44loCD62Lhi) from Gpr25+ / +(WT) and Gpr25- / -(KO) mice stimulated with anti-CD3 and anti-CD28 in the presence or absence of TGF-β for 24 hours. Representative histogram plots showing phosphorylation of Smad2(pS465 / pS467) / Smad3(pS423 / pS425) in the indicated samples. (FIG. 4K), Flow-cytometric analysis of naïve murine CD8+T cells (CD8+CD44loCD62Lhi) that were stimulated with anti-CD3 and anti-CD28 for 24h before transfection with pCMV-Thy1.1 (empty vector; EV) or pCMV-Gpr25-Thy1.1 (Gpr25), and then stimulated with TGF-β for 24 hours. Representative histogram plots showing phosphorylation of Smad2 / Smad3 in the indicated samples. Bar graphs in (FIGS. 4F – 4H, FIGS. 4J – 4K) depict mean, each symbol represents data from an individual mouse; all data from (FIGS. 4F – 4H, FIGS. 4J – 4K) are representative of two independent experiments. Statistical significance for the comparisons was computed using two-tailed two unequal variance Student t test; *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001. FIGS. 5A – 5H: Gpr25 promotes development of lung TRMcells. (FIG. 5A), Illustration of the lung TRM model in which congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred intratracheally at a 1:1 ratio into CD45.1 recipient mice before infection with LCMV-OVA delivered intratracheally (i.t.) (FIG. 5B), (FIG. 5C), Flow-cytometric analysis of cells isolated from lungs of recipient mice (n = 5) at 30 days post infection. (FIG. 5B), Representative contour plots and the frequencies of transferred Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells in lungs are shown. (FIG. 5C), Representative contour plots and frequencies of transferred Gpr25+ / +(WT) OT-I CD8+T cells, Gpr25- / -(KO) OT-I CD8+T cells and host CD8+T cells that express CD69 and CD103 (top), CD69 and CXCR6 (bottom) are shown; numbers adjacent to outlined areas (bottom) indicate frequencies of cells co-expressing CD69 and CXCR6. (FIGS. 5D – 5F), Single-cell RNA-seq analysis of Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells isolated from lungs of recipient mice (n = 6) at 30 days post infection. (FIG. 5D), Single-cell transcriptomes of Gpr25+ / +(WT; top) and Gpr25- / -(KO; bottom) OT-I CD8+T cells are displayed by uniform manifold approximation and projection (UMAP), using equal cell numbers for each group (n = 706). Seurat-based clustering of 2,102 cells colored based in cluster type; the proportion of cells each cluster is shown (right). (FIG. 5E), Plot shows Z-score average expression (color scale) and percentage of cells (size scale) expressing selected transcripts that Atty. Dkt. No.: 116639-2710 are differentially expressed in the two clusters (FDR ≤ 0.05, fold change > 0.25; full list of differentially expressed transcripts is provided in. (FIG. 5F), UMAPs illustrating Seurat- normalized expression levels of Il7r, Xcl1, Gpr183, Zeb2, S1pr5, Gzmb, and Cx3cr1 transcripts in single cells. (FIG. 5G), Illustration of the lung TRM model in which Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I CD8+T cells were transferred into independent cohorts of CD8KO recipient mice before infection with LCMV-OVA (i.t.). (FIG. 5H), Representative histograms and the frequencies of TCF1-expressing cells in Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I CD8+T cells. Bar graphs in (FIGS. 5B – 5C) depict mean, bar graphs in (FIG. 5H) depict mean ± S.D.; each symbol represents data from an individual mouse; all data from (FIG. 5B), (FIG. 5C) are representative of three independent experiments. Data from (FIG. 5H) are representative of two independent experiments. Statistical significance for the comparisons was computed using two- tailed two unequal variance Student t test; **P < 0.01. FIGS. 6A – 6G: Gpr25-deficient T cells fail to control lung metastasis. (FIG. 6A), Illustration of the lung metastasis model in which Gpr25+ / +(WT; CD45.1.2) OT-I CD8+T cells were transferred intratracheally (OT-I transfer group) into CD45.1 recipient mice before infection with LCMV-OVA (i.t.); Thirty days after infection, B16F10-OVA melanoma cells were injected intravenously. To compare with endogenous anti-tumor immune responses, a group of mice did not receive OT-I cells or LCMV-OVA infection (no transfer group). (FIG. 6B), Representative picture of lung metastatic nodules and number of nodules on the surface of 5 lobes assessed 13 days after tumor injection in mice from the OT-I transfer and no transfer group. (FIG. 6A), Illustration of the lung metastasis model in which congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred intratracheally at a 1:1 ratio into CD45.1 recipient mice before infection with LCMV-OVA (i.t.); Thirty days after infection, B16F10-OVA melanoma cells were injected intravenously into these mice. (FIG. 6B), Flow-cytometric analysis of CD8+T cells isolated from the lungs of recipient mice (n = 4) at 13 days after tumor injection. Representative contour plots and the frequencies of transferred Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells are shown. (FIG. 6C), (FIG. 6E), Illustration of the lung metastasis model in which Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I CD8+T cells were transferred intratracheally into two cohorts of (FIG. 6C) CD45.1 or (FIG. 6E) CD8KO recipient mice before infection with LCMV-OVA (i.t.). Thirty days after infection, B16F10-OVA melanoma cells were injected intravenously into these mice Atty. Dkt. No.: 116639-2710 and FTY720 was intraperitoneally administrated to mice at indicated time points. (FIG. 6D), Representative picture of lung metastatic nodules and number of nodules on the surface of 5 lobes, assessed 14 days after tumor injection, in the mice receiving Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells. (FIG. 6F), Survival curve of cohorts of CD8KO recipient mice that received Gpr25+ / +(WT), Gpr25- / -(KO) OT-I CD8+T cells or no adoptive transfer of OT-1 CD8+T cells. (FIG. 6G), Representative picture of lung metastatic nodules and number of nodules on the surface of 5 lobes, assessed 14 days after tumor injection, in mice from the OT-I transfer and no OT-1 transfer group. Bar graph in (FIG. 6B) depicts mean, graphs in (FIG. 6D), (FIG. 6G) depict mean ± S.D., each symbol represents data from an individual mouse; all data from (FIG. 6B) are representative of two independent experiments. Data from (FIG. 6F), (FIG. 6G) are pooled data from two independent experiments. Statistical significance for the comparisons in (FIG. 6B), (FIG. 6D), (FIG. 6G) was computed using two-tailed two unequal variance Student t test; *P < 0.05, **P < 0.01 and ***P < 0.001. Statistical significance for the comparisons in (FIG. 6F), was calculated using Kaplan-Meier test; *P < 0.0332. FIGS. 7A – 7B: Sequence analysis of GPR25 and flow cytometry gating strategies. (FIG. 7A), Alignment of human and mouse GPR25 (Genebank entries NP_005289.2, NP_001094986.1, respectively). Identical amino acid residues are shown as (*), homology as (:), and different residues shaded. Predicted transmembrane domain (TM helix) regions are indicated by the lines above the amino acid labels. (FIG. 7B), Flow-cytometric plots show sequential gating strategies for isolating CD8+CD69+and CD8+CD69−T cells present in spleen and liver (top panel), CD8α+CD8α+and CD8α+CD8β+T cells present in small intestinal intraepithelial lymphocytes (siIEL; bottom panel) of unmanipulated wild-type C57BL / 6J mice (> 90 days old), used in FIG. 1D. FIGS. 8A – 8E: Gpr25 promotes the development of liver TRMcells. (FIGS. 8A – 8C), Illustration of the TRM model in which congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred at a 1:1 ratio into CD45.1 recipient mice before infection with LCMV-OVA (i.p.). OT-I TRM cells (CD69+CD62L-KLRG1- ) were sorted from CD8+T cells isolated from liver, OT-I TEM (CD127+CD62L-) and OT-I TCM (CD127+CD62L+) cells were sorted from CD8+T cells isolated from spleen of recipient mice (n= 6) at 30 days post infection. (FIG. 8B), Representative contour plots show expression of CD69 Atty. Dkt. No.: 116639-2710 and CD62L in OT-I cells. c, Quantitative real-time PCR (qRT-PCR) analysis of Gpr25 (left) and S1pr1 (right) expression levels in the indicated T cell subsets from Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells. (FIG. 8D), (FIG. 8E), Congenically distinct Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I CD8+T cells were co-transferred at a 1:1 ratio into CD45.1 recipient mice before infection with LCMV-OVA (i.p.). Flow-cytometric analysis of CD8+T cells isolated from the liver and small intestinal intraepithelial lymphocytes (siIEL) of recipient mice at 90 days post infection; gating strategy for phenotyping transferred OT-I cells is shown in (FIG. 8D). (FIG. 8E), Representative contour plots and frequencies of transferred Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I CD8+T cells that express CD69 and CXCR6, CD69 and CD103 are shown for n = 6 mice (independent repeat of experiment shown in FIG. 2D); numbers adjacent to outlined areas (FIG. 8D) indicate frequencies of cells co-expressing CD69 and CXCR6. Bar graph in (FIG. 8C) depicts mean ± S.E.M., bar graph in (FIG. 8E) depicts mean, each symbol represents data from an individual mouse. Statistical significance for the comparisons was computed using two-tailed two unequal variance Student t test; *P < 0.05, **P < 0.01 and ***P < 0.001. FIGS. 9A – 9D: Gpr25 deficiency impairs early stages of TRMcell development. (FIGS.9A – 9D), Congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred at a 1:1 ratio into CD45.1 recipient mice before infection with LCMV-OVA (i.p.). Flow-cytometric analysis of CD8+T cells isolated from the liver of recipient mice (n= 5) at 24 hours, 48 hours, day 30 post infection. (FIG.9A), Frequencies of transferred Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells in liver at 24 and 48 hours post infection are shown. (FIG. 9B), Representative contour plots and frequencies of transferred Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I CD8+T cells that express CD66 and CD44 in liver at 24 and 48 hours are shown. (FIG.9C), Mean fluorescence intensity of CD25 expression in transferred Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I CD8+T cells at 24 hours post infection is shown. (FIG.9D), Representative contour plots show frequency of transferred Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I CD8+T cells in liver that express CD69, CD62L, CD44 and CD127 at 30 days post infection. Bar graphs in a-c depicts mean, each symbol represents data from an individual mouse. FIGS. 10A – 10D: Gpr25 promotes the development of secondary TRMcells. (FIG. 10A), Congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred at a 1:1 ratio into CD45.1 recipient mice before infection with Atty. Dkt. No.: 116639-2710 LCMV-OVA (i.p.). Single-cell RNA-seq was performed on Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I TRM cells (CD69+CD62L- KLRG1-) isolated from CD8+T cells in the liver of recipient mice (n= 8) at 30 days post infection. Expression levels of the indicated transcripts in Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I TRM cells are shown. (FIG. 10B), (FIG. 10D), Congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred at a 1:1 ratio into CD45.1 recipient mice before infection with LCMV- OVA (i.p.). Single-cell RNA-seq was performed on total Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I T cells isolated from liver of recipient mice (n= 8) at 12 days post infection. (FIG. 10B), Gene-set enrichment analysis (GSEA) plot shows enrichment of the indicated gene signatures in Gpr25+ / +(WT) when compared to Gpr25- / -(KO) T cells. False discovery rate (FDR) and normalized enrichment score (NES) were determined using fgsea package on R. (FIG. 10C), Congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I TRMcells, generated as described in FIG. 3A, were isolated from liver and co-transferred at a 1:1 ratio into CD45.1 naïve recipient mice before infection with LCMV-OVA (i.p.). Flow- cytometric analysis of CD8+T cells isolated from the liver of recipient mice (n= 4) at 30 days post infection. Representative contour plots and frequencies of transferred Gpr25+ / +(WT) and Gpr25- / -(KO) OT-I TRMcells in the liver that express CD69 and CD62L are shown. (FIG. 10D), GSEA plot shows positive enrichment of TGF-β response gene signatures, from the indicated source, in Gpr25+ / +(WT) OT-I when compared to Gpr25- / -(KO) OT-I T cells isolated from the liver 12 days post infection. False discovery rate (FDR) and normalized enrichment score (NES) were determined using fgsea package on R. Bar graph depicts mean, each symbol represents data from an individual mouse; all data are representative of two independent experiments, with n = 4 mice in each experiment. Statistical significance for the comparisons was computed using two- tailed two unequal variance Student t test; ***P < 0.001. FIGS. 11A – 11E: Gpr25 promotes development of lung TRMcells. (FIG.11A), Illustration of the TRMmodel in which congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred intravenously at a 1:1 ratio into CD45.1 recipient mice before infection with LCMV-OVA delivered intraperitoneally (i.p.) (FIGS.11B – 11C), Flow-cytometric analysis of cells isolated from lungs of recipient mice at 30 days (n = 5) and 120 days (n = 3) post infection. (FIG.11B), Representative contour plots and the frequencies of transferred Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells in the lungs are shown. (FIG.11C), Atty. Dkt. No.: 116639-2710 Representative contour plots and frequencies of transferred Gpr25+ / +(WT) OT-I CD8+T cells, Gpr25- / -(KO) OT-I CD8+T cells and host CD8+T cells in the lungs that express CD69 and CD103 are shown. (FIG.11D), Congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred intratracheally at a 1:1 ratio into CD45.1 recipient mice before infection with LCMV-OVA delivered intratracheally (i.t.). Flow-cytometric analysis of cells isolated from lungs of recipient mice (n = 6) at 30 days post infection. Representative contour plots and frequencies of transferred Gpr25+ / +(WT) OT-I CD8+T cells, Gpr25- / -(KO) OT-I CD8+T cells and host CD8+T cells that express CD69 and CD103 are shown (independent repeat of experiment shown in FIGS.5A – 5C). (FIG.11E), Single-cell RNA-seq analysis of Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells isolated from lungs of recipient mice (n = 6) at 30 days post infection. UMAPs illustrating Seurat-normalized expression levels of Cd27, Fasl, Gzma, Prf1 and Klrg1 transcripts in single cells. Bar graphs in (FIGS.11B – 11D) depict mean, each symbol from (FIGS.11B – 11D) represents data from an individual mouse. all data from (FIGS.11B – 11D) are representative of three independent experiments, with n = 3-6 mice in each experiment. Statistical significance for the comparisons was computed using two-tailed two unequal variance Student t test; *P < 0.05. FIGS. 12A – 12C: Gpr25-deficient T cells fail to control lung metastasis. (FIG. 12A), Illustration of the lung metastasis model. Gpr25+ / +(WT; CD45.1.2) OT-I CD8+T cells were transferred intratracheally (OT-I transfer group) into CD45.1 recipient mice before infection with LCMV-OVA (i.t.); Thirty days after infection, B16F10-OVA melanoma cells were injected intravenously. FTY720 or control PBS was intraperitoneally administrated to mice at indicated time points. (FIG. 12B), Picture of lung metastatic nodules and number of nodules assessed 13 days after tumor injection. (FIG. 12C), Representative contour plots and frequencies of total CD8+T cells in the tumors of mice from the indicated groups. Bar graphs in (FIG. 12B) depicts mean, graph in (FIG. 12C) depict mean ± S.D.; each symbol represents data from an individual mouse; all data from (FIGS. 12B – 12C) are representative of two independent experiments. Statistical significance for the comparisons was computed using two-tailed two unequal variance Student t test; *P < 0.05, **P < 0.01. FIG. 13. Ligand-Induced Forward Trafficking (LIFT) assay. Mutant oGPCR (blue) is retained in the ER. Chemical ligands that bind the target (1) facilitate transit from the ER through the Golgi (2) to the PM. Trafficking of the ligand:oGPCR complex to the PM leads to internalization via the early endosome (3), where the EA-tagged EEA1 protein resides. Atty. Dkt. No.: 116639-2710 Internalization brings the PK and EA tags together to form a functional enzyme. Exogenously added substrate is converted to light (4). The split β-gal enzyme fragments, PK and EA are shown in pink and green respectively. LU : Light. FIG. 14 illustrates a GPR25 Hit ID testing funnel. FIG. 15 illustrates a GPR25 lead generation plan. FIG. 16. Demonstrates quantitative real-time PCR (qRT-PCR) analysis of GPR25 expression levels in naïve human (left) and murine (right) CD8+ T cells stimulated with anti- CD3 and anti-CD28 in the presence or absence of TGF-β for 24 and 48 hours. Graphs depict mean ± S.E.M.; all data are representative of two independent experiments, with n = 5-11 in each experiment. Statistical significance was computed using two-tailed two unequal variance Student t test; *P < 0.05 and **P < 0.01. DETAILED DESCRIPTION OF THE DISCLOSURE Embodiments according to the present disclosure will be described more fully hereinafter. Aspects of the disclosure may, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art. The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All nucleotide sequences provided herein are presented in the 5′ to 3′ direction. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, particular, non-limiting exemplary methods, devices, and materials are now described. All technical and patent publications cited herein are incorporated herein by reference in their entirety. Nothing herein is to be construed as an admission that the disclosure is not entitled to antedate such disclosure by virtue of prior disclosure. Atty. Dkt. No.: 116639-2710 The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of tissue culture, immunology, molecular biology, microbiology, cell biology and recombinant DNA, which are within the skill of the art. See, e.g., Sambrook and Russell eds, (2001) Molecular Cloning: A Laboratory Manual, 3rd edition; the series Ausubel et al. eds. (2007) Current Protocols in Molecular Biology; the series Methods in Enzymology (Academic Press, Inc., N.Y.); MacPherson et al. (1991) PCR 1: A Practical Approach (IRL Press at Oxford University Press); MacPherson et al. (1995) PCR 2: A Practical Approach; Harlow and Lane eds. (1999) Antibodies, A Laboratory Manual; Freshney (2005) Culture of Animal Cells: A Manual of Basic Technique, 5th edition; Gait ed. (1984) Oligonucleotide Synthesis; U.S. Pat. No. 4,683,195; Hames and Higgins eds. (1984) Nucleic Acid Hybridization; Anderson (1999) Nucleic Acid Hybridization; Hames and Higgins eds. (1984) Transcription and Translation; Immobilized Cells and Enzymes (IRL Press (1986)); Perbal (1984) A Practical Guide to Molecular Cloning; Miller and Calos eds, (1987) Gene Transfer Vectors for Mammalian Cells (Cold Spring Harbor Laboratory); Makrides ed. (2003) Gene Transfer and Expression in Mammalian Cells; Mayer and Walker eds. (1987) Immunochemical Methods in Cell and Molecular Biology (Academic Press, London); and Herzenberg et al. eds (1996) Weir's Handbook of Experimental Immunology. The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The practice of the present technology will employ, unless otherwise indicated, conventional techniques of tissue culture, immunology, molecular biology, microbiology, cell biology, and recombinant DNA, which are within the skill of the art. Unless the context indicates otherwise, it is specifically intended that the various features of the disclosure described herein can be used in any combination. Moreover, the disclosure also contemplates that in some embodiments, any feature or combination of features set forth herein can be excluded or omitted. To illustrate, if the specification states that a Atty. Dkt. No.: 116639-2710 complex comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination. Unless explicitly indicated otherwise, all specified embodiments, features, and terms intend to include both the recited embodiment, feature, or term and biological equivalents thereof. All numerical designations, e.g., pH, temperature, time, concentration, and molecular weight, including ranges, are approximations which are varied ( + ) or ( - ) by increments of 1.0 or 0.1, as appropriate, or alternatively by a variation of + / - 15 %, or alternatively 10%, or alternatively 5%, or alternatively 2% and such ranges are included. It is to be understood, although not always explicitly stated, that all numerical designations are preceded by the term “about”. It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art. Throughout this disclosure, various publications, patents, and published patent specifications may be referenced by an identifying citation or by an Arabic numeral. The disclosures of these publications, patents and published patent specifications are hereby incorporated by reference into the present disclosure in their entirety to more fully describe the state of the art to which this disclosure pertains. Definitions As used in the description of the disclosure and the appended claims, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. As used herein, the term “comprising” is intended to mean that the compositions and methods include the recited elements, but do not exclude others. As used herein, the transitional phrase consisting essentially of (and grammatical variants) is to be interpreted as encompassing the recited materials or steps and those that do not materially affect the basic and novel characteristic(s) of the recited embodiment. Thus, the term “consisting essentially of” as used herein should not be interpreted as equivalent to “comprising”. “Consisting of” shall mean Atty. Dkt. No.: 116639-2710 excluding more than trace elements of other ingredients and substantial method steps for administering the compositions disclosed herein. Aspects defined by each of these transition terms are within the scope of the present disclosure. The term “about” as used herein when referring to a measurable value such as an amount or concentration and the like, is meant to encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount. As used herein, the terms “increased”, “decreased”, “high”, “low” or any grammatical variation thereof refer to a variation of about 90%, 80%, 50%, 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the reference composition, polypeptide, protein, etc. The terms or “acceptable,” “effective,” or “sufficient” when used to describe the selection of any components, ranges, dose forms, etc. disclosed herein intend that said component, range, dose form, etc. is suitable for the disclosed purpose. Also as used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”). An equivalent of a polynucleotide (referred to herein as the reference) shares at least 50% (or at least 60%, or at least 70%, or at least 80%, or at least 90%) identity to the reference, and encodes the same polypeptide as the one encoded by the reference, or encodes an equivalent of the polypeptide encoded by the reference. To arrive at a position or a consecutive segment of a test sequence equivalent to (or corresponding to) an / a amino acid / nucleotide residue or a consecutive segment of a reference sequence, a sequence alignment is performed between the test and reference sequences. The positions or segments aligned to each other are determined as equivalents. The term “analogue” refers to an equivalent having one or more modified amino acids and one or more amino acids replaced with another amino acid. Such modification may include but is not limited to conjugation with a molecule (for example, a small molecule, a cytotoxic molecule, a linker, a pH-sensitive linker, and / or a thiol linker), sialylation, Atty. Dkt. No.: 116639-2710 polysialylation, O-glycosylation, N-glycosylation, myristoylation, palmitoylation, isoprenylation or prenylation, glipyatyon, lipoylation, phosphopantetheinylation, ethanolamine phosphoglycerol attachment, diphthamide formation, hypusine formation, acylation, acetylation, formylation, alkylation, methylation, amidation, citrullination, deamidation, eliminylation, ISGylation, SUMOylation, ubiquitination, neddylation, pupylation, biotinylation, carbamylation, oxidation, pegylation, glycation, carbamylation, carbonylation, spontaneous isopeptide bond formation, butyrylation, gamma-carboxylation, malonylation, hydroxylation, iodination, nucleotide addition, phosphate ester (O-linked) or phosphoramidate (N-linked) formation, phosphorylation, adenylylation, uridylylation, propionylation, pyroglutamate formation, S-glutathionylation, S- nitrosylation, S-sulfenylation, S-sulfinylation, S-sulfonylation, succinylation, and / or sulfation. The term “albumin equivalent,” comprises, or consists essentially of, or yet further consists of, polypeptides which can be expressed at a reasonable quantity and which still retains or improves on certain albumin properties, including the binding of the albumin fragment to an FcRn receptor, as is known in the art or described herein. The term “affinity tag” refers to a polypeptide that may be included within a fusion protein to allow detection of the fusion protein and / or purification of the fusion protein from the cellular milieu using a ligand that is able to bind to, i.e., has affinity for, the affinity tag. The ligand may be, but is not limited to, an antibody, a resin, or a complementary polypeptide. An affinity tag may comprise a small peptide, commonly a peptide of approximately 4 to 16 amino acids in length, or it may comprise a larger polypeptide. Commonly used affinity tags include polyarginine, FLAG, V5, polyhistidine, c-Myc, Strep II, maltose binding protein (MBP), N-utilization substance protein A (NusA), thioredoxin (Trx), and glutathione S-transferase (GST), among others (for examples, see GST Gene Fusion System Handbook - Sigma-Aldrich). In an embodiment the affinity tag is a polyhistidine tag, for example a His6 tag. The inclusion of an affinity tag in a fusion protein allows the fusion protein to be purified from the cellular milieu by affinity purification, using an affinity medium that can tightly and specifically bind the affinity tag. The affinity medium may comprise, for example, a metal-charged resin or a ligand covalently linked to a stationary phase (matrix) such as agarose or metal beads. For example, polyhistidine tagged fusion proteins (also referred to as His tagged fusion proteins) can be recovered by immobilized metal ion chromatography using Ni2+or Co2+loaded resins, anti- Atty. Dkt. No.: 116639-2710 FLAG affinity gels may be used to capture FLAG tagged fusion proteins, and glutathione cross- linked to a solid support such as agarose may be used to capture GST tagged fusion proteins. As used herein the terms “purification”, “purifying”, or “separating” refer to the process of isolating one or more polypeptides from a complex mixture, such as a cell lysate or a mixture of polypeptides. The purification, separation, or isolation need not be complete, i.e., some components of the complex mixture may remain with the one or more polypeptides after the purification process. However, the product of purification should be enriched for the one or more polypeptides relative to the complex mixture before purification and a significant portion of the other components initially present within the complex mixture should be removed by the purification process. The term “cell” as used herein may refer to either a prokaryotic or eukaryotic cell, optionally obtained from a subject or a commercially available source. “Eukaryotic cells” comprise all of the life kingdoms except monera. They can be easily distinguished through a membrane-bound nucleus. Animals, plants, fungi, and protists are eukaryotes or organisms whose cells are organized into complex structures by internal membranes and a cytoskeleton. The most characteristic membrane-bound structure is the nucleus. Unless specifically recited, the term “host” includes a eukaryotic host, including, for example, yeast, higher plant, insect and mammalian cells. Non-limiting examples of eukaryotic cells or hosts include simian, bovine, porcine, murine, rat, avian, reptilian and human, e.g., HEK293 cells, Chinese Hamster Ovary (CHO) cells and 293T cells. “Prokaryotic cells” that usually lack a nucleus or any other membrane-bound organelles and are divided into two domains, bacteria and archaea. In addition to chromosomal DNA, these cells can also contain genetic information in a circular loop called an episome. Bacterial cells are very small, roughly the size of an animal mitochondrion (about 1-2 μm in diameter and 10 μm long). Prokaryotic cells feature three major shapes: rod shaped, spherical, and spiral. Instead of going through elaborate replication processes like eukaryotes, bacterial cells divide by binary fission. Examples include but are not limited to Bacillus bacteria, E. coli bacterium, and Salmonella bacterium. Atty. Dkt. No.: 116639-2710 The term “encode” as it is applied to nucleic acid sequences refers to a polynucleotide which is said to “encode” a polypeptide if, in its native state or when manipulated by methods well known to those skilled in the art, can be transcribed and / or translated to produce the mRNA for the polypeptide and / or a fragment thereof. The antisense strand is the complement of such a nucleic acid, and the encoding sequence can be deduced therefrom. As used herein, “expression” refers to the process by which polynucleotides are transcribed into mRNA and / or the process by which the transcribed mRNA is subsequently being translated into peptides, polypeptides, or proteins. If the polynucleotide is derived from genomic DNA, expression may include splicing of the mRNA in a eukaryotic cell. The term “isolated” or a grammatical variation thereof as used herein refers to molecules or biologicals or cellular materials being substantially free from other materials. As used herein, the term “functional” may be used to modify any molecule, biological, or cellular material to intend that it accomplishes a particular, specified effect. As used herein, the terms “nucleic acid sequence” and “polynucleotide” are used interchangeably to refer to a polymeric form of nucleotides of any length, either ribonucleotides or deoxyribonucleotides. Thus, this term includes, but is not limited to, single-, double-, or multi- stranded DNA or RNA, genomic DNA, complementary DNA (cDNA), DNA-RNA hybrids, or a polymer comprising purine and pyrimidine bases or other natural, chemically or biochemically modified, non-natural, or derivatized nucleotide bases. In certain embodiments, the polynucleotide comprises and / or encodes a messenger RNA (mRNA), a short hairpin RNA, and / or small hairpin RNA. In one embodiment, the polynucleotide is or encodes an mRNA. In certain embodiments, the polynucleotide is a double-strand (ds) DNA, such as an engineered ds DNA or a ds cDNA synthesized from a single-stranded RNA. The terms “polynucleotide” and “oligonucleotide” are used interchangeably and refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides or analogs thereof. Polynucleotides can have any three-dimensional structure and may perform any function, known or unknown. The following are non-limiting examples of polynucleotides: a gene or gene fragment (for example, a probe, primer, EST or SAGE tag), Atty. Dkt. No.: 116639-2710 exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, RNAi, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes and primers. A polynucleotide can comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure can be imparted before or after assembly of the polynucleotide. The sequence of nucleotides can be interrupted by non- nucleotide components. A polynucleotide can be further modified after polymerization, such as by conjugation with a labeling component. The term also refers to both double- and single- stranded molecules. Unless otherwise specified or required, any embodiment disclosed herein that is a polynucleotide encompasses both the double-stranded form and each of two complementary single-stranded forms known or predicted to make up the double-stranded form. A polynucleotide is composed of a specific sequence of four nucleotide bases: adenine (A); cytosine (C); guanine (G); thymine (T); and uracil (U) for thymine when the polynucleotide is RNA. Thus, the term “polynucleotide sequence” is the alphabetical representation of a polynucleotide molecule. This alphabetical representation can be input into databases in a computer having a central processing unit and used for bioinformatics applications such as functional genomics and homology searching. The term “isolated” or “recombinant” as used herein with respect to nucleic acids, such as DNA or RNA, refers to molecules separated from other DNAs or RNAs, respectively that are present in the natural source of the macromolecule as well as polypeptides. The term “isolated or recombinant nucleic acid” is meant to include nucleic acid fragments which are not naturally occurring as fragments and would not be found in the natural state. The term “isolated” is also used herein to refer to polynucleotides, polypeptides and proteins that are isolated from other cellular proteins and is meant to encompass both purified and recombinant polypeptides. In other embodiments, the term “isolated or recombinant” means separated from constituents, cellular and otherwise, in which the cell, tissue, polynucleotide, peptide, polypeptide, protein, antibody or fragment(s) thereof, which are normally associated in nature. For example, an isolated cell is a cell that is separated from tissue or cells of dissimilar phenotype or genotype. An isolated polynucleotide is separated from the 3′ and 5′ contiguous nucleotides with which it is normally associated in its native or natural environment, e.g., on the chromosome. As is apparent Atty. Dkt. No.: 116639-2710 to those of skill in the art, a non-naturally occurring polynucleotide, peptide, polypeptide, protein, antibody or fragment(s) thereof, does not require “isolation” to distinguish it from its naturally occurring counterpart. As used herein, the terms “engineered” “synthetic” “recombinant” and “non- naturally occurring” are interchangeable and indicate intentional human manipulation, for example, a modification from its naturally occurring form, and / or a sequence optimization. The terms “equivalent” or “biological equivalent” are used interchangeably when referring to a particular molecule, biological, or cellular material and intend those having minimal homology while still maintaining desired structure or functionality (for example, having a similar functional activity). It should be understood, without being explicitly stated that when referring to an equivalent or biological equivalent to a reference polypeptide, protein, or polynucleotide, that an equivalent or biological equivalent has the recited structural relationship to the reference polypeptide, protein, or polynucleotide and equivalent or substantially equivalent biological activity. For example, non-limiting examples of equivalent polypeptides, proteins, or polynucleotides include a polypeptide, protein, or polynucleotide having at least 60%, or alternatively at least 65%, or alternatively at least 70%, or alternatively at least 75%, or alternatively 80%, or alternatively at least 85%, or alternatively at least 90%, or alternatively at least 95% identity thereto or for polypeptide, polynucleotide, or protein sequences across the length of the reference polynucleotide. Alternatively, an equivalent polypeptide is one that is encoded by a polynucleotide or its complement that hybridizes under conditions of high stringency to a polynucleotide encoding such reference polypeptide sequences and that have substantially equivalent or equivalent biological activity. Conditions of high stringency are described herein and incorporated herein by reference. Alternatively, an equivalent thereof is a polypeptide encoded by a polynucleotide or a complement thereto, having at least 70%, or alternatively at least 75%, or alternatively 80%, or alternatively at least 85%, or alternatively at least 90%, or alternatively at least 95% identity, or at least 97% sequence identity across the length of the reference polynucleotide to the reference polynucleotide, e.g., the wild-type polynucleotide. Such equivalent polypeptides have the same biological activity as the reference polynucleotide. Atty. Dkt. No.: 116639-2710 Non-limiting examples of equivalent polypeptides, include a polynucleotide having at least 60%, or alternatively at least 65%, or alternatively at least 70%, or alternatively at least 75%, or alternatively 80%, or alternatively at least 85%, or alternatively at least 90%, or alternatively at least 95%, or alternatively at least 97%, identity to a reference polynucleotide. An equivalent also intends a polynucleotide or its complement that hybridizes under conditions of high stringency to a reference polynucleotide. Such equivalent polypeptides have the same biological activity as the reference polynucleotide. A polynucleotide or polynucleotide region (or a polypeptide or polypeptide region) having a certain percentage (for example, 80%, 85%, 90%, or 95%) of “sequence identity” to another sequence means that, when aligned, that percentage of bases (or amino acids) are the same in comparing the two sequences across the length of the reference polynucleotide. The alignment and the percent homology or sequence identity can be determined using software programs known in the art, for example those described in Current Protocols in Molecular Biology (Ausubel et al., eds. 1987) Supplement 30, section 7.7.18, Table 7.7.1. In certain embodiments, default parameters are used for alignment. A non-limiting exemplary alignment program is BLAST, using default parameters. In particular, exemplary programs include BLASTN and BLASTP, using the following default parameters: Genetic code=standard; filter=none; strand=both; cutoff=60; expect=10; Matrix=BLOSUM62; Descriptions=50 sequences; sort by=HIGH SCORE; Databases=non-redundant, GenBank+EMBL+DDBJ+PDB+GenBank CDS translations+SwissProtein+SPupdate+PIR. Details of these programs can be found at the following Internet address: ncbi.nlm.nih.gov / cgi- bin / BLAST. Sequence identity and percent identity can be determined by incorporating them into clustalW (available at the web address:genome.jp / tools / clustalw / , last accessed on Jan. 13, 2017). “Homology” or “identity” or “similarity” refers to sequence similarity between two peptides or between two nucleic acid molecules. Homology can be determined by comparing a position in each sequence that may be aligned for purposes of comparison. When a position in the compared sequence is occupied by the same base or amino acid, then the molecules are homologous at that position. A degree of homology between sequences is a function of the number of matching or homologous positions shared by the sequences. An “unrelated” or “non- Atty. Dkt. No.: 116639-2710 homologous” sequence shares less than 40% identity, or alternatively less than 25% identity, with one of the sequences of the present disclosure. As used herein, the term “at least 90% identical” refers to an identity of two compared sequences (polynucleotides or polypeptides) of about 90% to about 100%. It also include an identity of at least at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, about 91% to about 100%, about 92% to about 100%, about 93% to about 100%, about 94% to about 100%, about 95% to about 100%, about 96% to about 100%, about 97% to about 100%, about 98% to about 100%, or about 99% to about 100%. “Homology” or “identity” or “similarity” can also refer to two nucleic acid molecules that hybridize under stringent conditions. As used herein, the terms “retain” “similar” and “same” are used interchangeably while describing a function, an activity or a functional activity of a polynucleotide, a protein and / or a peptide, referring to a functional activity of at least about 20% (including but not limited to: at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or about 100%) of the activity of the reference protein, polynucleotide and / or peptide. It is to be inferred without explicit recitation and unless otherwise intended, that when the present disclosure relates to a polypeptide, protein, polynucleotide, or antibody, an equivalent or a biologically equivalent of such is intended within the scope of this disclosure. As used herein, the term “biological equivalent thereof” is intended to be synonymous with “equivalent thereof” when referring to a reference protein, antibody, fragment, polypeptide, or nucleic acid, intends those having minimal homology while still maintaining desired structure or functionality. Unless specifically recited herein, it is contemplated that any polynucleotide, polypeptide or protein mentioned herein also includes equivalents thereof. In one aspect, an equivalent polynucleotide is one that hybridizes under stringent conditions to the polynucleotide or complement of the polynucleotide as described herein for use in the described methods. In another aspect, an equivalent antibody or antigen binding polypeptide intends one that binds with at least 70%, or alternatively at least 75%, or alternatively at least 80%, or alternatively at least Atty. Dkt. No.: 116639-2710 85%, or alternatively at least 90%, or alternatively at least 95% affinity or higher affinity to a reference antibody or antigen binding fragment. In another aspect, the equivalent thereof competes with the binding of the antibody or antigen binding fragment to its antigen under a competitive ELISA assay. In another aspect, an equivalent intends at least about 80% homology or identity and alternatively, at least about 85%, or alternatively at least about 90%, or alternatively at least about 95%, or alternatively 98% percent homology or identity and exhibits substantially equivalent biological activity to the reference protein, polypeptide, or nucleic acid. “Hybridization” refers to a reaction in which one or more polynucleotides react to form a complex that is stabilized via hydrogen bonding between the bases of the nucleotide residues. The hydrogen bonding may occur by Watson-Crick base pairing, Hoogstein binding, or in any other sequence-specific manner. The complex may comprise two strands forming a duplex structure, three or more strands forming a multi-stranded complex, a single self-hybridizing strand, or any combination of these. A hybridization reaction may constitute a step in a more extensive process, such as the initiation of a PCR reaction, or the enzymatic cleavage of a polynucleotide by a ribozyme. Examples of stringent hybridization conditions include: incubation temperatures of about 25° C. to about 37° C.; hybridization buffer concentrations of about 6×SSC to about 10×SSC; formamide concentrations of about 0% to about 25%; and wash solutions from about 4×SSC to about 8×SSC. Examples of moderate hybridization conditions include: incubation temperatures of about 40° C. to about 50° C.; buffer concentrations of about 9×SSC to about 2×SSC; formamide concentrations of about 30% to about 50%; and wash solutions of about 5×SSC to about 2×SSC. Examples of high stringency conditions include: incubation temperatures of about 55° C. to about 68° C.; buffer concentrations of about 1×SSC to about 0.1×SSC; formamide concentrations of about 55% to about 75%; and wash solutions of about 1×SSC, 0.1×SSC, or deionized water. In general, hybridization incubation times are from 5 minutes to 24 hours, with 1, 2, or more washing steps, and wash incubation times are about 1, 2, or 15 minutes. SSC is 0.15 M NaCl and 15 mM citrate buffer. It is understood that equivalents of SSC using other buffer systems can be employed. Atty. Dkt. No.: 116639-2710 The term “protein”, “peptide” and “polypeptide” are used interchangeably and in their broadest sense to refer to a compound of two or more subunits of amino acids, amino acid analogs or peptidomimetics. The subunits may be linked by peptide bonds. In another aspect, the subunit may be linked by other bonds, e.g., ester, ether, etc. A protein or peptide must contain at least two amino acids and no limitation is placed on the maximum number of amino acids which may comprise a protein’s or peptide’s sequence. As used herein the term “amino acid” refers to either natural and / or unnatural or synthetic amino acids, including glycine and both the D and L optical isomers, amino acid analogs and peptidomimetics. As used herein, a consecutive amino acid sequence refers to a sequence having at least two amino acids. However, it is noted that a consecutive amino acid sequence of a first part and a second part does not limit the amino acid sequence to have the first part directly conjugated to the second part. It is also possible that the first part is linked to the second part via a third part, such as a link, thus forming one consecutive amino acid sequence. A polynucleotide disclosed herein can be delivered to a cell or tissue using a gene delivery vehicle. “Gene delivery,” “gene transfer” “mRNA-based delivery”, “transducing,” and the like as used herein, are terms referring to the introduction of an exogenous polynucleotide (sometimes referred to as a “transgene”) into a host cell, irrespective of the method used for the introduction. Such methods include a variety of well-known techniques such as vector-mediated gene transfer (by, e.g., viral infection / transfection, or various other protein-based or lipid-based gene delivery complexes, including for example protamine complexes, lipid nanoparticles, polymeric nanoparticles, lipid-polymer hybrid nanoparticles, and inorganic nanoparticles, or combinations thereof) as well as techniques facilitating the delivery of “naked” polynucleotides (such as electroporation, “gene gun” delivery and various other techniques used for the introduction of polynucleotides). The introduced polynucleotide can be unmodified or can comprise one or more modifications; for example, a modified mRNA may comprise ARCA capping; enzymatic polyadenylation to add a tail of 100-250 adenosine residues; and substitution of one or both of cytidine with 5-methylcytidine and / or uridine with pseudouridine. The introduced polynucleotide may be stably or transiently maintained in the host cell. Stable maintenance typically requires that the introduced polynucleotide either contains an origin of replication compatible with the host cell or integrates into a replicon of the host cell such as an Atty. Dkt. No.: 116639-2710 extrachromosomal replicon (e.g., a plasmid) or a nuclear or mitochondrial chromosome. A number of vectors are known to be capable of mediating transfer of genes to mammalian cells, as is known in the art and described herein. A “plasmid” is an extra-chromosomal DNA molecule separate from the chromosomal DNA which is capable of replicating independently of the chromosomal DNA. In many cases, it is circular and double-stranded. Plasmids provide a mechanism for horizontal gene transfer within a population of microbes and typically provide a selective advantage under a given environmental state. Plasmids may carry genes that provide resistance to naturally occurring antibiotics in a competitive environmental niche, or alternatively the proteins produced may act as toxins under similar circumstances. “Plasmids” used in genetic engineering are called “plasmid vectors”. Many plasmids are commercially available for such uses. The gene to be replicated is inserted into copies of a plasmid containing genes that make cells resistant to particular antibiotics and a multiple cloning site (MCS, or polylinker), which is a short region containing several commonly used restriction sites allowing the easy insertion of DNA fragments at this location. Another major use of plasmids is to make large amounts of proteins. In this case, researchers grow bacteria containing a plasmid harboring the gene of interest. Just as the bacterium produces proteins to confer its antibiotic resistance, it can also be induced to produce large amounts of proteins from the inserted gene. A “viral vector” is defined as a recombinantly produced virus or viral particle that comprises a polynucleotide to be delivered into a host cell, either in vivo, ex vivo or in vitro. Examples of viral vectors include retroviral vectors, adenovirus vectors, adeno- associated virus vectors, herpes simplex virus vectors, alphavirus vectors and the like. As used herein, the term “animal” refers to living multi-cellular vertebrate organisms, a category that includes, for example, mammals and birds. The term “mammal” includes both human and non-human mammals. In one aspect, a “subject” or “patient” to whom the therapies such as for example a combination of anti-GPR25 therapy and immune checkpoint inhibitor is administered is Atty. Dkt. No.: 116639-2710 preferably a mammal such as a non-primate (e.g., cow, pig, horse, cat, dog, rat, etc.) or a primate (e.g., monkey or human). The subject or patient can be a human, such as an adult patient or a pediatric patient. The term “subject” refers includes but is not limited to a subject at risk of cancer or an infection as well as a subject that has already developed cancer or infection. Such subjects, include mammalian animals (mammals), such as a non-human primate (apes, gibbons, gorillas, chimpanzees, orangutans, macaques), a domestic animal (dogs and cats), a farm animal (poultry such as chickens and ducks, horses, cows, goats, sheep, pigs), experimental animal (mouse, rat, rabbit, guinea pig) and humans. Subjects include animal disease models, for example, mouse and other animal models of cancer or an age-associated genome dysfunction, disorder, or disease known in the art. Accordingly, subjects appropriate for treatment include those having or at risk of cancer or an infection, also referred to as subjects in need of treatment. Subjects in need of treatment therefore include subjects that have been previously had cancer or an infection, or that have an ongoing cancer or an infection or have developed one or more adverse symptoms caused by or associated with cancer or an infection regardless of the type, timing or degree of onset, progression, severity, frequency, duration of the symptoms. Prophylactic uses and methods are therefore included. Target subjects for prophylaxis may be at increased risk (probability or susceptibility) of developing cancer or an infection. Such subjects are considered in need of treatment due to being at risk. Subjects for prophylaxis need not be at increased risk but may be from the general population in which it is desired to protect a subject against cancer or an infection for example. Such a subject that is desired to be protected against cancer or an infection can be administered treatment or agent described herein. In another non-limiting example, a subject that is not specifically at risk for cancer or an infection, but nevertheless desires protection against cancer or an infection can be administered a composition or agent as described herein. Such subjects are also considered in need of treatment. Atty. Dkt. No.: 116639-2710 “Prophylaxis” and grammatical variations thereof mean a method in which contact, administration or in vivo delivery to a subject is prior to development of cancer or an infection. In certain situations, it may not be known that a subject has developed cancer or an infection, but administration or in vivo delivery to a subject can be performed prior to manifestation of disease pathology or an associated adverse symptom, condition, complication, etc. caused by or associated with cancer or an infection. In such case, a composition or method of the present disclosure can eliminate, prevent, inhibit, suppress, limit, decrease or reduce the probability of or susceptibility to cancer or an infection, or an adverse symptom, condition or complication associated with or caused by cancer or an infection. “Prophylaxis” can also refer to a method in which contact, administration or in vivo delivery to a subject is prior to a secondary or subsequent exposure or infection. In such a situation, a subject may have had a prior cancer or an infection or prior adverse symptom, condition or complication associated with or caused by cancer or an infection. Treatment by administration or in vivo delivery to such a subject, can be performed prior to a secondary or subsequent cancer or an infection. Such a method can eliminate, prevent, inhibit, suppress, limit, decrease or reduce the probability of or susceptibility towards a secondary or subsequent cancer or an infection, or an adverse symptom, condition or complication associated with or caused by or associated with a secondary or subsequent cancer or an infection. Treatment of cancer or an infection can be at any time during the cancer or an infection. Certain embodiments of the present disclosure can be administered as a combination (e.g., with a second active), or separately concurrently or in sequence (sequentially) in accordance with the methods described herein as a single or multiple dose e.g., one or more times hourly, daily, weekly, monthly or annually or between about 1 to 10 weeks, or for as long as appropriate, for example, to achieve a reduction in the onset, progression, severity, frequency, duration of one or more symptoms or complications associated with or caused by cancer or an infection, or an adverse symptom, condition or complication associated with or caused by cancer or an infection. Thus, a method can be practiced one or more times (e.g., 1-10, 1-5 or 1-3 times) an hour, day, week, month, or year. The skilled artisan will know when it is appropriate to delay or discontinue administration. A non-limiting dosage schedule is 1-7 times per week, for 1, 2, 3, Atty. Dkt. No.: 116639-2710 4, 5, 6, 7, 8, 9, 10, 15, 20 or more weeks, and any numerical value or range or value within such ranges. An “effective amount” or “efficacious amount” refers to the amount of an agent, or combined amounts of two or more agents, that, when administered for the treatment of a mammal or other subject, is sufficient to effect such treatment for the disease. The “effective amount” will vary depending on the agent(s), the disease and its severity and the age, weight, etc., of the subject to be treated. Doses can vary and depend upon whether the treatment is prophylactic or therapeutic, whether a subject has previously had cancer or an infection, the onset, progression, severity, frequency, duration probability of or susceptibility of the symptom, condition, pathology or complication, the treatment protocol and compositions, the clinical endpoint desired, the occurrence of previous or simultaneous treatments, the general health, age, gender, race or immunological competency of the subject and other factors that will be appreciated by the skilled artisan. The skilled artisan will appreciate the factors that may influence the dosage and timing required to provide an amount sufficient for providing a therapeutic or prophylactic benefit. The dose amount, number, frequency, or duration may be proportionally increased or reduced, as indicated by the status of the subject. For example, whether the subject has previously had cancer or an infection, whether the subject is merely at risk of cancer or an infection, exposure or infection, whether the subject has been previously treated for cancer or an infection. The dose amount, number, frequency, or duration may be proportionally increased or reduced, as indicated by any adverse side effects, complications or other risk factors of the treatment or therapy. In the methods of the invention, the route, dose, number and frequency of administrations, treatments, and timing / intervals between treatment and disease development can be modified. In certain embodiments, a desirable treatment of the present disclosure will elicit robust, long-lasting immunity against cancer or an infection. Thus, in certain embodiments, disclosure methods, uses and compositions provide long-lasting immunity to cancer or an infection. Atty. Dkt. No.: 116639-2710 As used herein, a biological sample, or a sample, can be obtained from a subject, cell line or cultured cell or tissue. Exemplary samples include, but are not limited to, cell sample, tissue sample, tumor biopsy, liquid samples such as blood and other liquid samples of biological origin (including, but not limited to, ocular fluids (aqueous and vitreous humor), peripheral blood, sera, plasma, ascites, urine, cerebrospinal fluid (CSF), sputum, saliva, bone marrow, synovial fluid, aqueous humor, amniotic fluid, cerumen, breast milk, broncheoalveolar lavage fluid, semen, prostatic fluid, cowper’s fluid or pre-ejaculatory fluid, female ejaculate, sweat, tears, cyst fluid, pleural and peritoneal fluid, pericardial fluid, ascites, lymph, chyme, chyle, bile, interstitial fluid, menses, pus, sebum, vomit, vaginal secretions / flushing, synovial fluid, mucosal secretion, stool water, pancreatic juice, lavage fluids from sinus cavities, bronchopulmonary aspirates, blastocyl cavity fluid, or umbilical cord blood. In some instances, the sample is a tumor / cancer biopsy. A “solid tumor” is an abnormal mass of tissue that usually does not contain cysts or liquid areas. Solid tumors can be benign or malignant. Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors include sarcomas, carcinomas, and lymphomas. The solid tumor can be localized or metastatic. In certain embodiments, the terms “disease” “disorder” and “condition” are used interchangeably herein, referring to a cancer, a status of being diagnosed with a cancer, or a status of being suspected of having a cancer. As used herein, the term “extracellular matrix” (ECM) is a three-dimensional network of extracellular macromolecules, such as collagen, enzymes, and glycoproteins, that provide structural and biochemical support to surrounding cells. It is an essential component of the tumor microenvironment. Cancer development and progression are associated with increased ECM deposition and crosslink, while the chemical and physical signals elicited from ECM are necessary for cancer cell proliferation and invasion. In one embodiment, the ECM of a cancer comprises a peri-cancerous cell or tissue. As used herein, the term “detectable marker” refers to at least one marker capable of directly or indirectly, producing a detectable signal. A non-exhaustive list of this marker includes enzymes which produce a detectable signal, for example by colorimetry, fluorescence, Atty. Dkt. No.: 116639-2710 luminescence, such as horseradish peroxidase, alkaline phosphatase, β-galactosidase, glucose-6 phosphate, dehydrogenase, chromophores such as fluorescent, luminescent dyes, groups with electron density detected by electron microscopy or by their electrical property such as conductivity, amperometry, voltammetry, impedance, detectable groups, for example whose molecules are of sufficient size to induce detectable modifications in their physical and / or chemical properties, such detection may be accomplished by optical methods such as diffraction, surface plasmon resonance, surface variation, the contact angle change or physical methods such as atomic force spectroscopy, tunnel effect, or radioactive molecules such as32P,35S ,89Zr or125I. As used herein, the term “purification marker” refers to at least one marker useful for purification or identification. A non-exhaustive list of this marker includes His, lacZ, GST, maltose-binding protein, NusA, BCCP, c-myc, CaM, FLAG, GFP, YFP, cherry, thioredoxin, poly(NANP), V5, Snap, HA, chitin-binding protein, Softag 1, Softag 3, Strep, or S-protein. Suitable direct or indirect fluorescence marker comprise FLAG, GFP, YFP, RFP, dTomato, cherry, Cy3, Cy 5, Cy 5.5, Cy 7, DNP, AMCA, Biotin, Digoxigenin, Tamra, Texas Red, rhodamine, Alexa fluors, FITC, TRITC or any other fluorescent dye or hapten. As used herein, “immunophenotyping” refers to the analysis of heterogeneous populations of cells for the purpose of identifying the presence and proportions of the various populations in the sample. Antibodies are used to identify cells by detecting specific antigens (termed markers) expressed by these cells. In an aspect, the cell samples are characterized by immunophenotyping using techniques such as flow cytometry. In alternative aspects, characterizations of the various cell types, (such as T cells, B cells and their subsets) present in a cell sample may be carried out using any suitable methodology such as reverse transcriptase polymerase chain reaction (RT-PCR) or immunocytochemistry (IHC). The phrase “first line” or “second line” or “third line” or “fourth line” or “fifth line” refers to the order of treatment received by a patient. First-line therapy regimens are treatments given first, whereas second or third-line therapy are given after the first-line therapy or after the second-line therapy, respectively. The National Cancer Institute defines first-line therapy as “the first treatment for a disease or condition. In patients with cancer, primary Atty. Dkt. No.: 116639-2710 treatment can be surgery, chemotherapy, radiation therapy, or a combination of these therapies. First-line therapy is also referred to those skilled in the art as “primary therapy and primary treatment”. Typically, a patient is given a subsequent chemotherapy regimen because the patient did not show a positive clinical or sub-clinical response to the first-line therapy or the first-line therapy has stopped. As used herein, the term “T cell,” refers to a type of lymphocyte that matures in the thymus. T cells play an important role in cell-mediated immunity and are distinguished from other lymphocytes, such as B cells, by the presence of a T-cell receptor on the cell surface. T- cells may either be isolated or obtained from a commercially available source. “T cell” includes all types of immune cells expressing CD3 including T-helper cells (CD4+ cells), cytotoxic T- cells (CD8+ cells), natural killer T-cells, T-regulatory cells (Treg), Tissue-resident memory T cells (TRM cells), stem T cells and gamma-delta T cells. A “cytotoxic cell” includes CD8+ T cells, natural-killer (NK) cells, and neutrophils, which cells are capable of mediating cytotoxicity responses. Non-limiting examples of commercially available T-cell lines include lines BCL2 (AAA) Jurkat (ATCC® CRL-2902™), BCL2 (S70A) Jurkat (ATCC® CRL-2900™), BCL2 (S87A) Jurkat (ATCC® CRL-2901™), BCL2 Jurkat (ATCC® CRL-2899™), Neo Jurkat (ATCC® CRL-2898™), TALL-104 cytotoxic human T cell line (ATCC # CRL-11386). Further examples include but are not limited to mature T-cell lines, e.g., such as Deglis, EBT-8, HPB- MLp-W, HUT 78, HUT 102, Karpas 384, Ki 225, My-La, Se-Ax, SKW-3, SMZ-1 and T34; and immature T- cell lines, e.g., ALL-SIL, Be13, CCRF-CEM, CML-T1, DND-41, DU.528, EU-9, HD-Mar, HPB-ALL, H-SB2, HT-1, JK-T1, Jurkat, Karpas 45, KE-37, KOPT-K1, K-T1, L- KAW, Loucy, MAT, MOLT-1, MOLT 3, MOLT-4, MOLT 13, MOLT-16, MT-1, MT-ALL, P12 / Ichikawa, Peer, PER0117, PER-255, PF-382, PFI-285, RPMI-8402, ST-4, SUP-T1 to T14, TALL-1, TALL-101, TALL-103 / 2, TALL-104, TALL-105, TALL-106, TALL-107, TALL-197, TK-6, TLBR-1, -2, -3, and -4, CCRF-HSB-2 (CCL-120.1), J.RT3-T3.5 (ATCC TIB-153), J45.01 (ATCC CRL-1990), J.CaM1.6 (ATCC CRL-2063), RS4;11 (ATCC CRL-1873), CCRF-CEM (ATCC CRM-CCL-119); and cutaneous T-cell lymphoma lines, e.g., HuT78 (ATCC CRM-TIB- 161), MJ[G11] (ATCC CRL-8294), HuT102 (ATCC TIB-162). Null leukemia cell lines, including but not limited to REH, NALL-1, KM-3, L92-221, are another commercially available source of immune cells, as are cell lines derived from other leukemias and lymphomas, such as K562 erythroleukemia, THP-1 monocytic leukemia, U937 lymphoma, HEL erythroleukemia, Atty. Dkt. No.: 116639-2710 HL60 leukemia, HMC-1 leukemia, KG-1 leukemia, U266 myeloma. Non-limiting exemplary sources for such commercially available cell lines include the American Type Culture Collection, or ATCC, (http: / / www.atcc.org / ) and the German Collection of Microorganisms and Cell Cultures (https: / / www.dsmz.de / ). Tissue-Resident Memory T Cells, or TRM cells, refer to a subset of long-lived memory T cells that occupy various tissues without recirculating. TRM cells reside in tissues that create barriers against the outside environment and thus provide defense against repeatedly incoming pathogens. TRMs also play a role in the protection against malignancies. Three cell surface markers that has been associated with TRM are CD69, CD49a, and CD103. Transforming Growth Factor Beta, or TGF- β, is a growth and differentiation factor encoded by 33 genes in mammals and comprises homo- and heterodimers. “Frequency” of cells expressing any one particular molecule, biomarker, or antigen refers to the likelihood of or ratio of cells expressing the molecule, biomarker, or antigen compared to a population of T cells at large. G Protein-Coupled Receptor 25 (“GPR25) is a protein encoding gene that encodes a member of the G-protein coupled receptor 1 family. G-protein coupled receptors are membrane proteins which activate signaling cascades as a response to extracellular stress. Among its related pathways are GPCR downstream signaling and Class A / 1 (Rhodopsin-like receptors). The protein sequence of GPR25 is publicly available at https: / / useast.ensembl.org / Homo_sapiens / Transcript / Sequence_Protein?db=core;g=ENSG00000 170128;r=1:200872981-200874178;t=ENST00000304244 (accessed October 17, 2023) is reproduced below. MAPTEPWSPSPGSAPWDYSGLDGLEELELCPAGDLPYGYVYIPALYLAAFAVGLLGNAF VVWLLAGRRGPRRLVDTFVLHLAAADLGFVLTLPLWAAAAALGGRWPFGDGLCKLSS FALAGTRCAGALLLAGMSVDRYLAVVKLLEARPLRTPRCALASCCGVWAVALLAGLPS LVYRGLQPLPGGQDSQCGEEPSHAFQGLSLLLLLLTFVLPLVVTLFCYCRISRRLRRPPH VGRARRNSLRIIFAIESTFVGSWLPFSALRAVFHLARLGALPLPCPLLLALRWGLTIATCL AFVNSCANPLIYLLLDRSFRARALDGACGRTGRLARRISSASSLSRDDSSVFRCRAQAAN TASASW Atty. Dkt. No.: 116639-2710 The nucleic acid sequence encoding the GPR25 protein is publicly available https: / / www.ncbi.nlm.nih.gov / nuccore / NM_005298.4 (accessed October 17, 2023) reproduced below. 1 agagctgctg ccgcctgcgc ccagggctgc actccgcgca ggcctcatag ccaggccatg 61 gcccccacag agccctggag ccccagcccg gggtcagcgc cctgggacta ctcggggttg 121 gacggcctgg aggagctgga gctgtgtccg gccggggacc tgccctacgg ctacgtctac 181 atccccgcgc tctacctggc ggccttcgcc gtgggcctgc tgggcaacgc ctttgtggtg 241 tggctgctgg ccgggcggcg gggcccgcgg cggctggtgg ataccttcgt gctgcacctg 301 gcggcagctg acctgggctt cgtgctcacg ctgccgctgt gggccgcggc ggcggcgcta 361 ggcggccgct ggccgttcgg cgatggcctc tgcaagctca gcagcttcgc gctggcgggc 421 acgcgctgcg cgggcgcgct gctgctggcg ggcatgagcg tggaccgcta cctggccgtg 481 gtgaagctgc tcgaggcgag gccactgcgc accccgcgct gcgcgctggc ctcgtgctgc 541 ggcgtctggg ccgtggcgct gctggccggc ctgccctccc tggtctaccg ggggttgcag 601 cccctgcctg ggggccagga cagccagtgc ggcgaggagc cctcccacgc cttccagggc 661 ctcagcttgc tgctgctgct gctgaccttc gtgctgcccc tggtcgtcac cctcttctgc 721 tactgccgca tctcgcgccg cctgcgacgg ccgccgcacg tgggtcgggc ccggaggaac 781 tcgctgcgca tcatcttcgc catcgagagc acgtttgtgg gctcctggct gcccttcagc 841 gccctgcggg ccgtcttcca cctggcgcgt ctgggggcgc tgccgctgcc gtgccccctg 901 ctgctggcgc tgcgctgggg cctcaccatt gccacctgcc tggccttcgt caacagctgc 961 gccaacccgc tcatctacct cctgctggac cgctcattcc gagcccgggc gctggacggg 1021 gcctgcgggc gcaccggccg cctggcgcga aggatcagct cagcctcctc gctctccagg 1081 gacgacagtt ccgtgttccg ttgccgggcc caggccgcga acactgcctc ggcctcctgg 1141 tagctgcccc gggccgctgg aggtgggcgg cagcggagca tcgagaggag gccagagg Below are the murine and human amino acid sequence of GPR25. The homology of these sequences is provided in FIG. 7A. Mouse MQSTEPWSPSWGTLSWDYSGSGSLDQVELCPAWNLPYGHAIIPALYLAA FAVGLPGNAFVVWLLSRQRGPRRLVDTFVLHLAAADLGFVLTLPLWAAAEARGGLWP FGDGLCKVSSFALAVTRCAGALLLAGMSVDRYLAVGRPLSARPLRSARCVRAVCGAA WAAAFLAGLPALLYRGLQPSLDGVGSQCAEEPWEALQGVGLLLLLLTFALPLAVTLICY WRVSRRLPRVGRARSNSLRIIFTVESVFVGCWLPFGVLRSLFHLARLQALPLPCSLLLAL RWGLTVTTCLAFVNSSANPVIYLLLDRSFRARARFGLCARAGRQVRRISSASSLSRDDSS VFRGRSPKVNSASATW Human Atty. Dkt. No.: 116639-2710 MAPTEPWSPSPGSAPWDYSGLDGLEELELCPAGDLPYGYVYIPALYLAAF AVGLLGNAFVVWLLAGRRGPRRLVDTFVLHLAAADLGFVLTLPLWAAAAALGGRWPF GDGLCKLSSFALAGTRCAGALLLAGMSVDRYLAVVKLLEARPLRTPRCALASCCGVW AVALLAGLPSLVYRGLQPLPGGQDSQCGEEPSHAFQGLSLLLLLLTFVLPLVVTLFCYCR ISRRLRRPPHVGRARRNSLRIIFAIESTFVGSWLPFSALRAVFHLARLGALPLPCPLLLALR WGLTIATCLAFVNSCANPLIYLLLDRSFRARALDGACGRTGRLARRISSASSLSRDDSSV FRCRAQAANTASASW In general, agonistic antibodies and / or agents have the ability to bind and activate the target receptor in a way that mimics the activity of the ligand. The agent may include a small molecule, an antibody, lentivirus, adeno-associated virus, an antisense oligonucleotide, an siRNA or an miRNA. An agonistic anti GPR25 antibody intends an antibody, antigen binding fragment, derivative or other modification as described herein that recognizes and binds the GPR25 protein. The agonizing antibodies or agents described in the application may bind to GPR25 to increase, enhance, upregulate, and / or otherwise modulate the activity of the GPR25 receptor and / or the GPR25 expressing cell. Such activities may include proliferation and cell signaling activities of the cell upon which the GPR25 receptor is expressed. The agonistic antibodies or agents of this disclosure target and specifically bind to GPR25. In some aspects, the agonistic antibody or agents bind the receptor in a manner that mimics the binding of the physiological ligand resulting in antibody-mediated agonism. In some aspects, treatment with an agonistic anti- GPR25 antibodies significantly impedes tumor growth, which may be mediated via stimulation of tumor infiltrating CD8+ T cells. Immunotherapies utilizing agonistic antibodies or agents, especially those targeting trimeric receptors like 4-1BB or CD40, require antibody crosslinking via Fcg receptors expressed on APCs for efficient T cell activation. Depending on the Immunoglobulin (IgG) antibody subclass, they bind to and can thus get crosslinked by Fcg receptors with different affinities. (Li et al., 2011; Nimmerjahn et al., 2005; Claus et al., 2019) Thus, the antibody subclass and the availability, type, and degree of expression of Fcg receptors on APCs are critical determinants of immunotherapy treatment efficacy. However, the agonistic activity of antibodies targeting co-stimulatory receptors depends on a variety of factors and does not always require Fc cross-linking. Such factors include but are not limited to antibody affinity, Atty. Dkt. No.: 116639-2710 Fc modifications like glycoengineering or point mutations, the antibody subclass and antigen expression. As used herein, the terms “antibody,” “antibodies” and “immunoglobulin” includes whole antibodies and any antigen binding fragment or a single chain thereof. Thus the term “antibody” includes any protein or peptide containing molecule that comprises at least a portion of an immunoglobulin molecule. The terms “antibody,” “antibodies” and “immunoglobulin” also include immunoglobulins of any isotype, fragments of antibodies which retain specific binding to antigen, including, but not limited to, Fab, Fab′, F(ab)2, Fv, scFv, dsFv, Fd fragments, dAb, VH, VL, VhH, and V-NAR domains; minibodies, diabodies, triabodies, tetrabodies and kappa bodies; multispecific antibody fragments formed from antibody fragments and one or more isolated. Examples of such include, but are not limited to a complementarity determining region (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework (FR) region, or any portion thereof, at least one portion of a binding protein, chimeric antibodies, humanized antibodies, single-chain antibodies, and fusion proteins comprising an antigen- binding portion of an antibody and a non-antibody protein. The variable regions of the heavy and light chains of the immunoglobulin molecule contain a binding domain that interacts with an antigen. The constant regions of the antibodies (Abs) may mediate the binding of the immunoglobulin to host tissues. The term “anti-” when used before a protein name, anti-GPR25 for example, refers to a monoclonal or polyclonal antibody that binds and / or has an affinity to a particular protein. The antibodies can be polyclonal, monoclonal, multispecific (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired biological activity. Antibodies can be isolated from any suitable biological source, e.g., murine, rat, sheep and canine. The term “antibody fragment” refers to a portion of an intact antibody and refers to the antigenic determining variable regions of an intact antibody. In some embodiments, the term “antibody fragment” refers to at least one portion of an intact antibody, or recombinant variants thereof, and refers to the antigen binding domain, e.g., an antigenic determining variable Atty. Dkt. No.: 116639-2710 region of an intact antibody, that is sufficient to confer recognition and specific binding of the antibody fragment to a target, such as an antigen. Examples of antibody fragments include, but are not limited to, Fab, Fab′, F(ab′)2, Fv fragments, scFv antibody fragments, linear antibodies, single domain antibodies such as sdAb (either VL or VH), camelid VHH domains, and multi- specific antibodies formed from antibody fragments such as a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, and an isolated CDR or other epitope binding fragments of an antibody. An antigen binding fragment can also be incorporated into single domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, Nature Biotechnology 23:1126-1136, 2005). Antigen binding fragments can also be grafted into scaffolds based on polypeptides such as a fibronectin type III (Fn3)(see U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide minibodies). “Fab” means a monovalent antigen- binding fragment of an immunoglobulin that is composed of the light chain and part of the heavy chain. F(ab′)2 means a bivalent antigen-binding fragment of an immunoglobulin that contains both light chains and part of both heavy chains. As used herein, the term “Fv fragment” or “variable domain fragment” refers to a VH domain and a VL domain of an antibody specifically binding to an antigen, both domains forming together a Fv fragment. In some embodiment, Fv fragments mean an antibody fragment comprising the VHand VLdomains of an antibody, wherein these domains are present in a single polypeptide chain. Generally, the Fv fragment polypeptide further comprises a polypeptide linker between the VH and VL domains polypeptide that enables the scFv to form. The term “scFv” refers to a fusion protein comprising at least one antibody fragment comprising a variable region of a light chain and at least one antibody fragment comprising a variable region of a heavy chain, wherein the light and heavy chain variable regions are contiguously linked via a short flexible polypeptide linker, and capable of being expressed as a single chain polypeptide, and wherein the scFv retains the specificity of the intact antibody from which it is derived. Unless specified, as used herein an scFv may have the VL and VH variable regions in either order, e.g., with respect to the N-terminal and C-terminal ends of the polypeptide, the scFv may comprise VL-linker-VHor may comprise VH-linker-VL. Atty. Dkt. No.: 116639-2710 As used herein, the term “antibody heavy chain” refers to the larger of the two types of polypeptide chains present in all antibody molecules in their naturally occurring conformations. As used herein, the term “antibody light chain” refers to the smaller of the two types of polypeptide chains present in all antibody molecules in their naturally occurring conformations. Kappa (κ) and lambda (λ) light chains refer to the two major antibody light chain isotypes. As used herein, the term “synthetic antibody” means an antibody, which is generated using recombinant DNA technology, such as, for example, an antibody expressed by a bacteriophage. The term should also be construed to mean an antibody, which has been generated by the synthesis of a DNA molecule encoding the antibody and which DNA molecule expresses an antibody protein, or an amino acid sequence specifying the antibody, wherein the DNA or amino acid sequence has been obtained using synthetic DNA or amino acid sequence technology which is available and well known in the art. As used herein, the term “antibody variant” includes synthetic and engineered forms of antibodies which are altered such that they are not naturally occurring, e.g., antibodies that comprise at least two heavy chain portions but not two complete heavy chains (such as, domain deleted antibodies or minibodies); multi-specific forms of antibodies (e.g., bi-specific, tri-specific, etc.) altered to bind to two or more different antigens or to different epitopes on a single antigen); heavy chain molecules joined to scFv molecules and the like. In addition, the term “antibody variant” includes multivalent forms of antibodies (e.g., trivalent, tetravalent, etc., antibodies that bind to three, four or more copies of the same antigen. As used herein, the term “antigen” or “Ag” is defined as a molecule that provokes an immune response. This immune response may involve either antibody production, or the activation of specific immunologically-competent cells, or both. The skilled artisan will understand that any macromolecule, including virtually all proteins or peptides, can serve as an antigen. Furthermore, antigens can be derived from recombinant or genomic DNA. A skilled artisan will understand that any DNA, which comprises a nucleotide sequence or a partial nucleotide sequence encoding a protein that elicits an immune response therefore encoding an Atty. Dkt. No.: 116639-2710 “antigen” as that term is used herein. Furthermore, one skilled in the art will understand that an antigen need not be encoded solely by a full-length nucleotide sequence of a gene. It is readily apparent that the present invention includes, but is not limited to, the use of partial nucleotide sequences of more than one gene and that these nucleotide sequences are arranged in various combinations to elicit a desired immune response. Moreover, the skilled artisan will understand that an antigen need not be encoded by a “gene” at all. It is readily apparent that an antigen can be generated synthesized or can be derived from a biological sample. Such a biological sample can include, but is not limited to a tissue sample, a tumor sample, a cell or a biological fluid. The term “bispecific antibody” refers to an antibody that can simultaneously bind to two different receptors, epitopes or antigens. The bispecific antibodies of the instant disclosure may target and bind antigens on the same cells or different cells. In some aspects, the bispecific antibodies bind to GPR25 and a second molecule on the T cell. GPR25 may be expressed on a T cell. In some aspects, the second molecule is expressed on the same T cell. In one aspect, the bispecific antibodies of the claimed disclosure increase target specificity for GPR25 expressing T cells, while limiting undesirable off-target activity. In some aspects, the bispecific bind and modulate the expression or activity of GPR25 in or on the T cell or the GPR25 expressing T cells. In some other aspects as described herein, the bispecific antibodies bind to GPR25 and a tumor or cancer antigen expressed by a tumor or cancer cell, including but not limited to tumor-associated antigens or tumor-specific antigens. The bispecific antibody may simultaneously bind and activate the GPR25 expressing T cell, while also binding to a tumor or cancer antigen. Thus, the activated T cell is able to target the tumor or cancer cells expressing the antigen. In some aspects the antigen is overexpressed or specifically expressed by the tumor or cancer cell. Therefore, the bispecific antibodies of the present disclosure can be configured to bind to overexpressed or specifically expressed tumor or cancer antigens, including tumor- associated or tumor-specific antigens, that are identifiable markers of the tumor or cancer cell, rather than undesirably binding to off-target cells and antigens. As used herein, “monoclonal antibody” refers to an antibody obtained from a substantially homogeneous antibody population. Monoclonal antibodies are highly specific, as Atty. Dkt. No.: 116639-2710 each monoclonal antibody is directed against a single determinant on the antigen. The antibodies may be detectably labeled, e.g., with a radioisotope, an enzyme which generates a detectable product, a fluorescent protein, and the like. The antibodies may be further conjugated to other moieties, such as members of specific binding pairs, e.g., biotin (member of biotin-avidin specific binding pair), and the like. The antibodies may also be bound to a solid support, including, but not limited to, polystyrene plates or beads, and the like. Monoclonal antibodies may be generated using hybridoma techniques or recombinant DNA methods known in the art. A hybridoma is a cell that is produced in the laboratory from the fusion of an antibody-producing lymphocyte and a non-antibody producing cancer cell, usually a myeloma or lymphoma. A hybridoma proliferates and produces a continuous sample of a specific monoclonal antibody. Alternative techniques for generating or selecting antibodies include in vitro exposure of lymphocytes to antigens of interest, and screening of antibody display libraries in cells, phage, or similar systems. The term “human antibody” as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies disclosed herein may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term “human antibody” as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. Thus, as used herein, the term “human antibody” refers to an antibody in which substantially every part of the protein (e.g., CDR, framework, CL, CHdomains (e.g., CH1, CH2, CH3), hinge, (VL, VH)) is substantially non-immunogenic in humans, with only minor sequence changes or variations. Similarly, antibodies designated primate (monkey, baboon, chimpanzee, etc.), rodent (mouse, rat, rabbit, guinea pig, hamster, and the like) and other mammals designate such species, sub-genus, genus, sub-family, family-specific antibodies. Further, chimeric antibodies include any combination of the above. Such changes or variations optionally retain or reduce the immunogenicity in humans or other species relative to non- modified antibodies. Thus, a human antibody is distinct from a chimeric or humanized antibody. It is pointed out that a human antibody can be produced by a non-human animal or prokaryotic Atty. Dkt. No.: 116639-2710 or eukaryotic cell that is capable of expressing functionally rearranged human immunoglobulin (e.g., heavy chain and / or light chain) genes. Further, when a human antibody is a single-chain antibody, it can comprise a linker peptide that is not found in native human antibodies. For example, an Fv can comprise a linker peptide, such as two to about eight glycine or other amino acid residues, which connects the variable region of the heavy chain and the variable region of the light chain. Such linker peptides are considered to be of human origin. As used herein, a human antibody is “derived from” a particular germline sequence if the antibody is obtained from a system using human immunoglobulin sequences, e.g., by immunizing a transgenic mouse carrying human immunoglobulin genes or by screening a human immunoglobulin gene library. A human antibody that is “derived from” a human germline immunoglobulin sequence can be identified as such by comparing the amino acid sequence of the human antibody to the amino acid sequence of human germline immunoglobulins. A selected human antibody typically is at least 90% identical in amino acids sequence to an amino acid sequence encoded by a human germline immunoglobulin gene and contains amino acid residues that identify the human antibody as being human when compared to the germline immunoglobulin amino acid sequences of other species (e.g., murine germline sequences). In certain cases, a human antibody may be at least 95%, or even at least 96%, 97%, 98%, or 99% identical in amino acid sequence to the amino acid sequence encoded by the germline immunoglobulin gene. Typically, a human antibody derived from a particular human germline sequence will display no more than 10 amino acid differences from the amino acid sequence encoded by the human germline immunoglobulin gene. In certain cases, the human antibody may display no more than 5, or even no more than 4, 3, 2, or 1 amino acid differences from the amino acid sequence encoded by the germline immunoglobulin gene. A “human monoclonal antibody” refers to antibodies displaying a single binding specificity which have variable and constant regions derived from human germline immunoglobulin sequences. The term also intends recombinant human antibodies. Methods for making these antibodies are described herein. In one embodiment, an antibody as used herein may be a recombinant antibody. The term “recombinant human antibody”, as used herein, includes all human antibodies that are Atty. Dkt. No.: 116639-2710 prepared, expressed, created or isolated by recombinant means, such as antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom, antibodies isolated from a host cell transformed to express the antibody, e.g., from a transfectoma, antibodies isolated from a recombinant, combinatorial human antibody library, and antibodies prepared, expressed, created or isolated by any other means that involve splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo. Methods for making these antibodies are described herein. As used herein, chimeric antibodies are antibodies whose light and heavy chain genes have been constructed, typically by genetic engineering, from antibody variable and constant region genes belonging to different species. As used herein, the term “humanized antibody” or “humanized immunoglobulin” refers to a human / non-human chimeric antibody that contains a minimal sequence derived from non-human immunoglobulin. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a variable region of the recipient are replaced by residues from a variable region of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity and capacity. Humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. The humanized antibody can optionally also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin, a non-human antibody containing one or more amino acids in a framework region, a constant region or a CDR, that have been substituted with a correspondingly positioned amino acid from a human antibody. In general, humanized antibodies are expected to produce a reduced immune response in a human host, as compared to a non-humanized version of the same antibody. The humanized Atty. Dkt. No.: 116639-2710 antibodies may have conservative amino acid substitutions which have substantially no effect on antigen binding or other antibody functions. Conservative substitutions groupings include: glycine-alanine, valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine- valine, serine-threonine and asparagine-glutamine. The antibodies of the present disclosure may bind to an antigen or molecule. In some aspects, the antigens or molecules are expressed in a T cell, tumor cell, or tissue of a subject. The terms “polyclonal antibody” or “polyclonal antibody composition” as used herein refer to a preparation of antibodies that are derived from different B-cell lines. They are a mixture of immunoglobulin molecules secreted against a specific antigen, each recognizing a different epitope. As used herein, the term “antibody derivative”, comprises a full-length antibody or a fragment of an antibody, wherein one or more of the amino acids are chemically modified by alkylation, pegylation, acylation, ester formation or amide formation or the like, e.g., for linking the antibody to a second molecule. This includes, but is not limited to, pegylated antibodies, cysteine-pegylated antibodies, and variants thereof. Complementarity-determining regions (CDRs) are part of the variable region of an antibody or a T cell receptor generated by B-cell s and T-cells respectively, wherein these molecules bind to their specific antigen (also called epitope). In certain embodiments, the terms “variable region” and “variable domain” are used interchangeably, referring to the polypeptide of a light or heavy chain of an antibody that varies greatly in its sequence of amino acid residues from one antibody to another, and that determines the conformation of the combining site which confers the specificity of the antibody for a particular antigen. In a further embodiment, the variable region is about 90 amino acids long to about 200 amino acids long, including but not limited to about 100 amino acids long, or alternatively about 110 amino acids long, or alternatively about 120 amino acids long, or alternatively about 130 amino acids long, or alternatively about 140 amino acids long, or alternatively about 150 amino acids long, or alternatively about 160 amino acids long, or alternatively about 170 amino acids long, or alternatively about 180 amino acids long, or alternatively about 190 amino acids long. In certain embodiments, a variable region of an amino acid sequence, as used herein, refers to the first Atty. Dkt. No.: 116639-2710 about 100 amino acids, or alternatively about 110 amino acids, or alternatively about 120 amino acids, or alternatively about 130 amino acids, or alternatively about 140 amino acids, or alternatively about 150 amino acids of the amino acid sequence (including or excluding a signal peptide if applicable) is the variable region. A set of CDRs constitutes a paratope also called an antigen-binding site, which is a part of an antibody that recognizes and binds to an antigen. There are three CDRs (CDR1, CDR2 and CDR3), arranged non-consecutively, optionally from the amino terminus to the carboxyl terminus, on the amino acid sequence of a variable region of an antigen receptor, such as a heavy chain or a light chain. As used herein, CDRn refers to a CDRn in an immunoglobulin chain or derived from an immunoglobulin chain, wherein the number n is selected from 1-3. In one embodiment, CDRLn refers to a CDRn in a light chain or derived from a light chain, wherein the number n is selected from 1-3; while CDRHn refers to a CDRn in a heavy chain or derived from a heavy chain, wherein the number n is selected from 1-3. In certain embodiments, framework region (FR) refers to the part of a variable region which is not a CDR. In certain embodiments, FRn refers to a FR in a heavy chain or a light chain or derived from a heavy chain or a light chain, and wherein the number n is selected from 1-4. In certain embodiments, a variable region comprises or consists essentially of, or yet further consists of the following (optionally following the order as provided, and further optionally from the amino terminus to the carboxyl terminus): FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. Variable regions and / or CDRs of an antibody or a fragment thereof can be determined by one of skill in the art, for example, using publically or commercially available tools. Non-limiting examples of such tools include, IgBlast (accessible at www.ncbi.nlm.nih.gov / igblast / ), Scaligner (available from drugdesigntech at www.scaligner.com / ), IMGT rules and / or tools (see, for example, www.imgt.org / IMGTScientificChart / Nomenclature / IMGT-FRCDRdefinition.html, also accessible at www.imgt.org / ), Chothia Canonical Assignment (accessible at www.bioinf.org.uk / abs / chothia.html), Antigen receptor Numbering And Receptor Classification (ANARCI, accessible at opig.stats.ox.ac.uk / webapps / newsabdab / sabpred / anarci / ), the Kabat numbering method / scheme (e.g., Kabat, E.A., et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Atty. Dkt. No.: 116639-2710 Publication No. 91-3242,) or the Paratome web server (accessible at www.ofranlab.org / paratome / , see Vered Kunik, et al, Nucleic Acids Research, Volume 40, Issue W1, 1 July 2012, Pages W521–W524). In general, agonistic antibodies have the ability to bind and activate the target receptor in a way that mimics the activity of the ligand. An agonistic anti-GPR25 antibody (anti- GPR25 antibody) intends an antibody, antigen-binding fragment, derivative or other modification as described herein that recognizes and binds the GPR25protein. The agonizing antibodies described in the application may bind to GPR25 to increase, enhance, upregulate, and / or otherwise modulate the activity of the GPR25 receptor and / or the GPR25 expressing cell. Such activities may include proliferation and cell signaling activities of the cell upon which the GPR25 receptor is expressed. The agonistic antibodies of this disclosure target and specifically bind to GPR25. In some aspects, the agonistic antibody binds the receptor in a manner that mimics the binding of the physiological ligand resulting in antibody-mediated agonism. In some aspects, treatment with an agonistic anti-GPR25 antibodies significantly impedes tumor growth, which may be mediated via stimulation of tumor-infiltrating CD8+ T cells. Immunotherapies utilizing agonistic antibodies, especially those targeting trimeric receptors like 4-1BB or CD40, require antibody crosslinking via Fcg receptors expressed on APCs for efficient T cell activation. Depending on the Immunoglobulin (IgG) antibody subclass, they bind to and can thus get crosslinked by Fcg receptors with different affinities. (Li et al., 2011; Nimmerjahn et al., 2005; Claus et al., 2019) Thus, the antibody subclass and the availability, type and degree of expression of Fcg receptors on APCs are critical determinants of immunotherapy treatment efficacy. However, the agonistic activity of antibodies targeting co-stimulatory receptors depends on a variety of factors and does not always require Fc cross-linking. Such factors include but are not limited to antibody affinity, Fc modifications like glycoengineering or point mutations, the antibody subclass and antigen expression. “Immune response” broadly refers to the antigen-specific responses of lymphocytes to foreign substances. The terms “immunogen” and “immunogenic” refer to molecules with the capacity to elicit an immune response. All immunogens are antigens, however, not all antigens are immunogenic. An immune response disclosed herein can be humoral (via antibody activity) or cell-mediated (via T cell activation). The response may occur Atty. Dkt. No.: 116639-2710 in vivo or in vitro. The skilled artisan will understand that a variety of macromolecules, including proteins, nucleic acids, fatty acids, lipids, lipopolysaccharides and polysaccharides have the potential to be immunogenic. The skilled artisan will further understand that nucleic acids encoding a molecule capable of eliciting an immune response necessarily encode an immunogen. The artisan will further understand that immunogens are not limited to full-length molecules, but may include partial molecules. As used herein, the term “inducing an immune response in a subject” or “modulating an immune response” are terms well understood in the art and intends that an increase or decrease of at least about 2-fold, at least about 5-fold, at least about 10-fold, at least about 100-fold, at least about 500-fold, or at least about 1000-fold or more in an immune response (i.e. T cell or antibody response) to an antigen (or epitope) and can be detected or measured by various methods known in the art. For example, the frequency or activity of antigen-specific T cells can be measured by multiple methods, including, but not limited to, flow cytometry, RNA-sequencing or in vitro assays. As used herein, the term “modulating activity” refers to increasing or decreasing the activity of specific T cell populations associated with an immune response. Modulating of activity may be accomplished by the administration of agents, including antibodies, that target and bind to specific T cell receptors in order to activate the T cell population expressing that molecule. Modulation may occur when the T cells are engaged by costimulatory ligands, agonistic antibodies or cytokines. In some aspects, modulating activity may include the administration of an agent that targets a molecule on a T cell. In some aspects, the molecule is GPR25and the agent is an antibody that targets GPR25, thus activating the GPR25expressing T cell. An “immunotherapy agent” means a type of cancer treatment which uses a patient’s own immune system to fight cancer, including but not limited to a physical intervention, a chemical substance, a biological molecule or particle, a cell, a tissue or an organ, or any combinations thereof, enhancing or activating or initiating a patient's immune response against cancer. Non-limiting examples of immunotherapy agents include antibodies, immune regulators, checkpoint inhibitors, an antisense oligonucleotide (ASO), an RNA interference Atty. Dkt. No.: 116639-2710 (RNAi), a Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) system, a viral vector, an anti-cancer cell therapy (e.g., transplanting an anti-cancer immune cell optionally amplified and / or activated in vivo, or administering an immune cell expressing a chimeric antigen receptor (CAR)), a CAR therapy, and cancer vaccines. As used herein, immune checkpoint refers to a regulator and / or modulator of the immune system (such as an immune response, an anti-tumor immune response, a nascent anti- tumor immune response, an anti-tumor immune cell response, an anti-tumor T cell response, and / or an antigen recognition of T cell receptor in the process of immune response). Their interaction activates either inhibitory or activating immune signaling pathways. Thus a checkpoint may contain one of the two signals: an stimulatory immune checkpoint that stimulates an immune response, and an inhibitory immune checkpoint inhibiting an immune response. In some embodiments, the immune checkpoint is crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. However, some cancers can protect themselves from attack by stimulating immune checkpoint targets. In some embodiments, the immune checkpoints are present on T cells, antigen-presenting cells (APCs) and / or tumor cells. As used herein, the term “recombinant host cell,” “recombinant cell,” “engineered host cell,” or “engineered cell,” means a cell into which a recombinant expression vector has been introduced. It should be understood that such terms are intended to refer not only to the particular subject cell but to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term “host cell” or “cell” as used herein. Host cells include progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or in total DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation and / or change. A host cell includes a cell transfected or infected in vivo or in vitro with a recombinant vector, an expression vector, or a nucleic acid encoding an antibody of the present disclosure. A host cell, which comprises a recombinant vector, expression vector, or a nucleic acid encoding an antibody disclosed herein, may also be referred to as a “recombinant host cell,” “engineered host cell,” or “engineered cell”. Atty. Dkt. No.: 116639-2710 As used herein, the term “host cell” refers to a cell, which may be used in a process for purifying an immunogenic protein or recombinant antibody in accordance with the present disclosure. Such host cell expresses the protein of interest (the antibody disclosed herein). A host cell may also be referred to as a protein-expressing cell. “Host cell” refers not only to the particular subject cell but to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein. A host cell, according to the present disclosure, may be, but is not limited to, prokaryotic cells, eukaryotic cells, archeobacteria, bacterial cells, insect cells, yeast, mammal cells, and / or plant cells. Bacteria envisioned as host cells can be either gram-negative or gram- positive, e.g. Escherichia coli, Erwinia sp., Klebsellia sp., Lactobacillus sp. or Bacillus subtilis. In some embodiments, the host cell is a yeast cell. In that embodiment, the yeast host cell is selected from the group consisting of Saccharomyces cerevisiae, Hansenula polymorpha, and Pichia pastoris. A “composition” is intended to mean a combination of active an agent and another compound or composition, inert (for example, a detectable agent or label) or active, such as an adjuvant , diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like and include pharmaceutically acceptable carriers. Carriers also include pharmaceutical excipients and additives proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, di-, tri, tetra-oligosaccharides, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides or sugar polymers), which can be present singly or in combination, comprising alone or in combination 1-99.99% by weight or volume. Exemplary protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acid / antibody components, which can also function in a buffering capacity, include alanine, arginine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like. Carbohydrate excipients are also intended within the scope of this technology, examples of which include but are not limited to Atty. Dkt. No.: 116639-2710 monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol) and myoinositol. A “pharmaceutical composition” is intended to include the combination of an active polypeptide, polynucleotide or antibody with a carrier, inert or active such as a solid support, making the composition suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo. “Pharmaceutically acceptable carriers” refers to any diluents, excipients, or carriers that may be used in the compositions disclosed herein. Pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. They may be selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. “Administration” can be effected in one dose, continuously or intermittently throughout the course of treatment. Methods of determining the most effective means and dosage of administration are known to those of skill in the art and will vary with the composition used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician. Suitable dosage formulations and methods of administering the agents are known in the art. Route of administration can also be determined and the method of determining the most effective route of administration is known to those of skill in the art and will vary with the composition used for treatment, the purpose of the treatment, the health condition or disease stage of the subject being treated, and target cell or tissue. Non-limiting Atty. Dkt. No.: 116639-2710 examples of routes of administration include oral administration, nasal administration, injection, and topical application. An agent of the present disclosure can be administered for therapy by any suitable route of administration. It will also be appreciated that the optimal route will vary with the condition and age of the recipient, and the disease being treated. The term “effective amount” refers to a quantity sufficient to achieve a desired effect. In the context of therapeutic or prophylactic applications, the effective amount will depend on the type and severity of the condition at issue and the characteristics of the individual subject, such as general health, age, sex, body weight, and tolerance to pharmaceutical compositions. With respect to immunogenic compositions, in some embodiments, the effective amount will depend on the intended use, the degree of immunogenicity of a particular antigenic compound, and the health / responsiveness of the subject's immune system, in addition to the factors described above. The skilled artisan will be able to determine appropriate amounts depending on these and other factors. In the case of an in vitro application, in some embodiments, the effective amount will depend on the size and nature of the application in question. It will also depend on the nature and sensitivity of the in vitro target and the methods in use. The skilled artisan will be able to determine the effective amount based on these and other considerations. The effective amount may comprise one or more administrations of a composition depending on the embodiment. “Simultaneous use” as used herein refers to the administration of the two compounds of the composition according to the disclosure in a single and identical pharmaceutical form or at the same time in two distinct pharmaceutical forms. “Separate use” as used herein refers to the administration, at the same time, of the two compounds of the composition according to the disclosure in distinct pharmaceutical forms. “Sequential use” as used herein refers to the successive administration of the two compounds of the composition according to the disclosure, each in a distinct pharmaceutical form. Atty. Dkt. No.: 116639-2710 The term “adjuvant” therapy refers to administration of a therapy or chemotherapeutic regimen to a patient in addition to the primary or initial treatment, such as after removal of a tumor by surgery. Adjuvant therapy is typically given to minimize or prevent a possible cancer reoccurrence. Alternatively, “neoadjuvant” therapy refers to administration of therapy or chemotherapeutic regimen before surgery, typically in an attempt to shrink the tumor prior to a surgical procedure to minimize the extent of tissue removed during the procedure. Additionally or alternatively, such adjuvant therapy potentials (i.e., sensitizes the subject to the original therapy) the subject may help reach one or more of clinical end points of the cancer treatment. The term “tissue” is used herein to refer to tissue of a living or deceased organism or any tissue derived from or designed to mimic a living or deceased organism. The tissue may be healthy, diseased, and / or have genetic mutations. The biological tissue may include any single tissue (e.g., a collection of cells that may be interconnected) or a group of tissues making up an organ, or part or region of the body of an organism. The tissue may comprise a homogeneous cellular material or it may be a composite structure such as that found in regions of the body including the thorax which for instance can include lung tissue, skeletal tissue, and / or muscle tissue. Exemplary tissues include, but are not limited to those derived from liver, lung, thyroid, skin, pancreas, blood vessels, bladder, kidneys, brain, biliary tree, duodenum, abdominal aorta, iliac vein, heart and intestines, including any combination thereof. As used herein, “treating” or “treatment of” a condition, disease, disorder or symptoms associated with a condition, disease or disorder refers to an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of condition, disorder or disease, stabilization of the state of condition, disorder or disease, prevention of development of condition, disorder or disease, prevention of the spread of condition, disorder or disease, delay or slowing of condition, disorder or disease progression, delay or slowing of condition, disorder or disease onset, amelioration or palliation of the condition, disorder or disease state, and remission, whether partial or total. “Treating” can also mean prolonging the survival of a subject beyond that expected in the absence of treatment. “Treating” can also mean inhibiting the progression of the condition, Atty. Dkt. No.: 116639-2710 disorder or disease, slowing the progression of the condition, disorder or disease temporarily, although in some instances, it involves halting the progression of the condition, disorder or disease permanently. Thus in the disclosed method, treatment can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of an established disease, condition, or symptom of the disease or condition. For example, a method for treating a disease is considered to be a treatment if there is a 10% reduction in one or more symptoms of the disease in a subject as compared to a control. Thus the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percent reduction in between 10% and 100% as compared to native or control levels. It is understood that treatment does not necessarily refer to a cure or complete ablation of the disease, condition, or symptoms of the disease or condition. Further, as used herein, references to decreasing, reducing, or inhibiting include a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater as compared to a control level and such terms can include but do not necessarily include complete elimination. The compositions used in accordance with the disclosure can be packaged in dosage unit form for ease of administration and uniformity of dosage. The term "unit dose" or "dosage" refers to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of the composition calculated to produce the desired responses in association with its administration, i.e., the appropriate route and regimen. The quantity to be administered, both according to a number of treatments and unit dose, depends on the result and / or protection desired. Precise amounts of the composition also depend on the judgment of the practitioner and are peculiar to each individual. Factors affecting dose include physical and clinical state of the subject, route of administration, intended goal of treatment (alleviation of symptoms versus cure), and potency, stability, and toxicity of the particular composition. Upon formulation, solutions are administered in a manner compatible with the dosage formulation and in such amount as is therapeutically or prophylactically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described herein. As used herein, the term “specifically binds,” with respect to an antibody, means an antibody or binding fragment thereof (e.g., Fv fragment or scFv) which recognizes a specific antigen, but does not substantially recognize or bind other molecules in a sample. For example, Atty. Dkt. No.: 116639-2710 an antibody that specifically binds to an antigen from one species may also bind to that antigen from one or more species. But, such cross-species reactivity does not itself alter the classification of an antibody as specific. In another example, an antibody that specifically binds to an antigen may also bind to different allelic forms of the antigen. However, such cross reactivity does not itself alter the classification of an antibody as specific. In some instances, the terms “specific binding” or “specifically binding,” can be used in reference to the interaction of an antibody, a protein, a chimeric antigen receptor, or a peptide with a second chemical species, to mean that the interaction is dependent upon the presence of a particular structure (e.g., an antigenic determinant or epitope) on the chemical species; for example, a chimeric antigen receptor recognizes and binds to a specific protein structure rather than to proteins generally. If an antibody is specific for epitope “A,” the presence of a molecule containing epitope A (or free, unlabeled A), in a reaction containing labeled “A” and the antibody, will reduce the amount of labeled A bound to the antibody. In some embodiments, the Fv fragment further comprises a linker domain to generate a single chain variable fragment (scFv). In one embodiment, the linker domain is operably linked to the heavy chain variable domain and the light chain variable domain. In some embodiments, the light and heavy chain variable regions are contiguously linked via a short flexible polypeptide linker, and capable of being expressed as a single chain polypeptide, and the scFv retains the specificity of the intact antibody from which it is derived. In one embodiment, the flexible polypeptide linker includes, but is not limited to, (Gly4 Ser)4 or (Gly4 Ser)3. In another embodiment, the linker includes multiple repeats of (Gly2Ser), (GlySer) or (Gly3Ser). MODES FOR CARRYING OUT THE DISCLOSURE Methods Disclosed herein are methods of treating cancer, determining the prognosis of a subject having cancer, determining the responsiveness of a subject to cancer therapy that modulates GPR25, or treating or ameliorating an infection in a subject. Also disclosed herein are methods for screening for a GPR25 anticancer therapy. The methods provide one or more of: (1) preventing the symptoms or disease from occurring in a subject that is predisposed or does not yet display symptoms of the disease; Atty. Dkt. No.: 116639-2710 (2) inhibiting the disease or arresting its development; or (3) ameliorating or causing regression or relapse of the disease or the symptoms of the disease. As understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. For the purposes of the present technology, beneficial or desired results can include one or more, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of the extent of a condition (including a disease), stabilized (i.e., not worsening) state of a condition (including disease), delay or slowing of condition (including disease), progression, amelioration or palliation of the condition (including disease), states and remission (whether partial or total), whether detectable or undetectable. Treatments containing the disclosed compositions and methods can be first-line, second-line, third-line, fourth-line, fifth-line therapy and are intended to be used as a sole therapy or in combination with other appropriate therapies. In alternative aspects, the disclosure provides methods of administering an agent capable of modulating the expression or activity of GPR25 in a T cell in the patient. In one aspect, this method comprises, or consists essentially of, or yet further consists of administering to the patient an agent that comprises, consists of, or consists essentially of a small molecule or a protein selected from the group of TGF-β. In some aspects, the T cell comprises, consists of, or consists essentially of: an activated T cell; a tissue-resident memory (TRM) cell; and a stem T cell. In some aspects, the activated T cell is specific for a tumor-specific antigen or a tumor- associated antigen expressed by the cancer or tumor cell, wherein the tumor-associated antigen is optionally overexpressed by the tumor cell. In some aspects, the modulation comprises, consists of, or consists essentially of activating the T cell by agonizing the expression or activity of GPR25 in the T cell. In further aspects, the agent comprises, consists of, or consists essentially of a bispecific agent that binds to GPR25 and binds to a second receptor expressed by the T cell. In some aspects the second receptor comprises, consists of, or consists essentially of CXCR5, CXCR6, CD8, CD103, CD49A, CD69, CD3, CD28, CD8 or PD1. In some aspects, the second receptor comprises CXCR5. In yet another aspect, the agent comprises, consists of, or consists essentially of a bispecific antibody that binds to GPR25 and the second molecule expressed by the T cell. Atty. Dkt. No.: 116639-2710 In yet another aspect, the agent that binds to GPR25 comprises, consists of, or consists essentially of an agonistic antibody. In yet another aspect, the agent comprises, consists of, or consists essentially of a bispecific antibody that binds to GPR25 and the second molecule expressed by the T cell. In yet another aspect, the agent binds to GPR25 and binds to a tumor antigen expressed by the tumor cell. In some aspects, the tumor antigen is overexpressed by the tumor cell. In some aspects, the tumor antigen comprises, consists of, or consists essentially of a tumor- associated antigen or a tumor-specific antigen. In some aspects, the tumor antigen comprises, consists of, or consists essentially of a tumor-associated antigen or a tumor-specific antigen. In some aspects, the tumor-associated antigen is overexpressed by the tumor cell. In some aspects, the tumor antigen comprises, consists of, or consists essentially of a lung cancer antigen or a lymphatic tissue antigen. In some aspects, the tumor antigen comprises, consists of, or consists essentially of MAGE-D4B, PSMA, HER2, HER3, EGFR, AFP, CEA, CA-125, MUC-1, ETA, MUC-1, BAGE, GAGE-1, MAGE-A1, NY-ESO-1, Gp100, Melan-A / MART-1, Prostate-specific antigen, Mammaglobin-A, Alpha-fetoprotein, HER-2 / neu, P53, K-ras, or TRP-2 / INT2 In some aspects, the cancer or tumor cell and / or the cancer or tumor comprises, consists of, or consists essentially of cancer or tumor of a tissue or cell from the group of: circulatory system; respiratory tract; gastrointestinal system genitourinary tract; live; bone; nervous system; reproductive system; hematologic system; oral cavity; skin and other tissues comprising connective and soft tissue, retroperitoneum and peritoneum, eye, intraocular melanoma, and adnexa, breast, head or / and neck, anal region, thyroid, parathyroid, adrenal gland and other endocrine glands and related structures, and lymph nodes, optionally wherein the cancer is a solid tumor or alternatively wherein the cancer is a liquid cancer, and further optionally wherein the cancer is a primary cancer or a metastasis and / or a cancer selected from a carcinoma, a sarcoma, a myeloma, a leukemia, or lymphoma, testis cancer, brain cancer, a metastasis or recurring cancer a non-small cell lung cancer (NSCLC) and / or head and neck squamous cell cancer (HNSCC). In some aspects, the cancer or tumor cell and / or the cancer or tumor comprises, consists of, or consists essentially of a cancer or tumor of a tissue or cell from the respiratory tract or lymph nodes. In some aspects, the cancer comprises, consists of, or consists essentially of a localized or metastatic cancer. Atty. Dkt. No.: 116639-2710 In some aspects, the patient is a human patient. In some aspects, the patient has reduced expression of GPR25 compared to that of a healthy, non-diseased subject. In some aspects, the methods further comprise, consist of, or consist essentially of resecting the tumor or cancer prior to modulating the expression or activity of GPR25 in the T cell in the patient. In some aspects, the modulating expression or activity of GPR25 in a T cell is administered as a first-line, a second-line, a third-line, a fourth-line or fifth-line therapy. In some aspects, the methods further comprise, consist of, or consist essentially of administering an effective amount of a different anti-cancer agent to the patient. In some aspects, the treating cancer or a tumor in a cancer patient comprises, consists of, or consists essentially of one or more of a reduction in tumor burden, longer overall survival or prolonged time to tumor progression. In yet another aspect, provided herein is a method for screening for a GPR25 anticancer therapy comprising, consisting of, or consisting essentially of contacting a first sample of T cells with an amount of the test agent that binds to GPR25 and a second agent that binds a tumor antigen, and assaying for increased expression of GPR25 in the T cell. In some aspects, increased expression of GPR25 in the T cell is an indication that the agent is a GPR25 anticancer therapy. In yet another aspect, provided herein is a method of modulating GPR25 in a subject, the method comprising, consisting of, or consisting essentially of administering a bispecific antibody that targets and binds to GPR25 and a second receptor expressed by a T cell. In some aspects, the receptor comprises, consists of, or consists essentially of CXCR5, CXCR6, CD8, CD103, CD49A, CD69, CD3, or PD1. In some aspects, the T cell comprises, consists of, or consists essentially of a stem T cell. In some aspects, the patient is a human patient. In yet another aspect, provided herein is a method of determining prognosis of a subject having cancer comprising, consisting of, or consisting essentially contacting T cells isolated from the subject with an antibody or agent that recognizes and binds to GPR25 to determine the frequency of T cells expressing GPR25 in tumor cells, wherein a high density of GPR25 in T cells indicates a more positive prognosis or wherein a low density of GPR25 in T cells indicates a more negative prognosis. In some aspects, the more negative prognosis Atty. Dkt. No.: 116639-2710 comprises, consists of, or consists essentially of a decreased probability of survival, and wherein the more positive prognosis comprises, consists of, or consists essentially of an increased probability of survival. In yet another aspect, provided herein is a method of determining the responsiveness of a subject to cancer therapy that modulates GPR25 comprising, consisting of, or consisting essentially contacting T cells isolated from the subject with an antibody or agent that recognizes and binds to GPR25 to determine the frequency of GPR25 expressing T cells in the subject, wherein a high frequency of GPR25 T cells indicates an increased likelihood of responsiveness to a cancer therapy. In some aspects, the cancer therapy comprises, consists of, or consists essentially of an agent that modulates the expression and / or activity of GPR25 in the subject. In some aspects, the density of GPR25 in T cells in the subject is compared to a healthy, non-diseased subject. In some aspects, the methods further comprise, consist of, or consist essentially of administering a cancer therapy that modulates GPR25 to the subject. In some aspects, the cancer therapy comprises, consists of, or consists essentially of an agent that binds to GPR25. In some aspects, the agent comprises, consists of, or consists essentially of an agonistic antibody targeting GPR25. In some aspects, the sample is contacted with an agent. In some aspects, the agent comprises, consists of, or consists essentially of a detectable label or tag. In some aspects, the detectable label or tag comprises, consists of, or consists essentially of a radioisotope, a metal, horseradish peroxidase, alkaline phosphatase, avidin or biotin. In some aspects, the agent comprises, consists of, or consists essentially of a polypeptide that binds to an expression product encoded by GPR25, or a polynucleotide that hybridizes to a nucleic acid sequence encoding all or a portion of GPR25. In some aspects, the polypeptide comprises, consists of, or consists essentially an antibody, an antigen-binding fragment thereof, or a receptor that binds to the GPR25. In some aspects, the antibody comprises, consists of, or consists essentially of an IgG, IgA, IgM, IgE or IgD, or a subclass thereof. In some aspects, the IgG comprises, consists of, or consists essentially of IgG1, IgG2, IgG3 or IgG4. In some aspects, the antigen binding fragment Atty. Dkt. No.: 116639-2710 comprises, consists of, or consists essentially of a Fab, Fab’, F(ab’)2, Fv, Fd, single-chain Fvs (scFv), disulfide-linked Fvs (sdFv) or VL or VH. In some aspects, the agent is contacted with the sample in conditions favoring the binding of the agent to GPR25. In some aspects of the methods disclosed herein, the agent is contacted with the sample in conditions favoring the binding of the agent to GPR25. In some aspects, the methods comprise, consist of, or consist essentially of detection by immunohistochemistry (IHC), in-situ hybridization (ISH), ELISA, immunoprecipitation, immunofluorescence, chemiluminescence, radioactivity, X-ray, nucleic acid hybridization, protein-protein interaction, immunoprecipitation, flow cytometry, Western blotting, polymerase chain reaction, DNA transcription, Northern blotting and / or Southern blotting. In some aspects, the sample comprises, consists of, or consists essentially of cells, tissue, an organ biopsy, an epithelial tissue, a lung, respiratory or airway tissue or organ, a circulatory tissue or organ, a skin tissue, bone tissue, muscle tissue, head, neck, brain, skin, bone and / or blood sample. In yet another aspect, provided herein is a method of treating cancer in a subject, comprising, consisting of, or consisting essentially of administering a T cell having increased expression of GPR25 to the subject. In some aspects, the cancer or tumor cell and / or the cancer or tumor comprises, consists of, or consists essentially of a cancer or tumor of a tissue or cell from the respiratory tract or lymph nodes. In some aspects, the cancer or tumor cell and / or the cancer or tumor comprises, consists of, or consists essentially of a cancer or tumor of a tissue or cell from the respiratory tract or lymph nodes a cancer or tumor of a tissue or cell from the respiratory tract. In some aspects, the cancer or tumor cell and / or the cancer or tumor comprises, consists of, or consists essentially of a metastatic cancer. In some aspects, the metastatic cancer comprises, consists of, or consists essentially of metastatic lung cancer. In some aspects, the patient is a human patient. In some aspects, the patient has reduced expression of GPR25 compared to that of a healthy, non-diseased subject. In some aspects, the T cell comprises, consists of, or consists essentially of an activated T cell; a tissue-resident memory (TRM) cell; a stem T cell. In some aspects, the activated T cell is specific for a tumor-specific antigen or a Atty. Dkt. No.: 116639-2710 tumor-associated antigen expressed by the tumor cell, wherein the tumor-associated antigen is optionally overexpressed by the tumor cell. In some aspects, the T cell comprises, consists of, or consists essentially of a TRM cell. In yet another aspect, provided herein are methods of promoting the development of TRM cells and / or stem-like TRM cells in a subject. In some aspects, the methods comprise, consist of, or consist essentially of administering an agent that modulates expression of GPR25 to the subject. In some aspects, the TRM cells are in the lung tissue or liver tissue of the subject. In some aspects, the agent is administered to the lung tissue or liver tissue of the subject. In some aspects, the agent comprises, consists of, or consists essentially of a small molecule or a protein selected from the group of: Transforming Growth Factor-β (TGF-β), Nuclear Factor of Activated T-cells (NFAT), or Suppressor of Mothers Against Decapentaplegic family member 1 (SMAD1), or equivalents thereof. Kits Finally, provided herein is a kit comprising, or consisting essentially of, or yet further consisting of one or more of the isolated T-cells and / or the composition of this disclosure and instructions for use. In one particular aspect, the present disclosure provides kits for performing the methods of this disclosure as well as instructions for carrying out the methods of the present disclosure. The kits are useful for diagnosing cancer in a subject from a biological sample taken from the subject e.g., any bodily fluid including, but not limited to, e.g., sputum, serum, plasma, lymph, cystic fluid, urine, stool, cerebrospinal fluid, acitic fluid or blood and including biopsy samples of body tissue. The test sample used in the above-described method will vary based on the assay format, nature of the detection method and the tissues, cells or extracts used as the sample to be assayed. Methods for preparing protein extracts or membrane extracts of cells are known in the art and can be readily adapted in order to obtain a sample which is compatible with the system utilized. The kit components, (e.g., reagents) can be packaged in a suitable container. The kit can also comprise, or alternatively consist essentially of, or yet further consist of, e.g., a Atty. Dkt. No.: 116639-2710 buffering agent, a preservative or a protein-stabilizing agent. The kit can further comprise, or alternatively consist essentially of, or yet further consist of components necessary for detecting the detectable label, e.g., an enzyme or a substrate. The kit can also contain a control sample or a series of control samples, which can be assayed and compared to the test sample. Each component of the kit can be enclosed within an individual container and all of the various containers can be within a single package, along with instructions for interpreting the results of the assays performed using the kit. The kits of the present disclosure may contain a written product on or in the kit container. The written product describes how to use the reagents contained in the kit. As amenable, these suggested kit components may be packaged in a manner customary for use by those of skill in the art. For example, these suggested kit components may be provided in solution or as a liquid dispersion or the like. EXPERIMENTAL EXAMPLES Example 1: Introduction Immunological memory is a hallmark of adaptive immunity and the basis of vaccination7. Tissue-resident memory CD8+T (TRM) cells are a distinct population of memory T cells that primarily reside within tissues and respond immediately against pathogens invading barrier tissues, thus representing the first line of defense1,2. TRM cells are phenotypically, functionally, transcriptionally, and metabolically distinct from circulating memory T cell subsets8-12like central memory T (TCM) and effector memory T (TEM) cells. For example, TRMcells lack expression of molecules required for tissue egress and trafficking to lymph nodes like S1PR1, S1PR5, C-C motif chemokine receptor (CCR)7 and CD62L2,13, and mostly express high levels of CD69, CD49a, and C-X-C motif chemokine receptor (CXCR)6, which play important roles in the tissue retention and localization of TRM cells14-16. The majority of TRM cells that reside within the epithelium also express the ⍺E integrin, CD1038,17, whereas, TRM cells that reside in non-epithelial tissues, such as liver10,15and kidney18,19do not express high levels of CD10310,15,20,21, presumably reflecting the lack of tight junctions in the sinusoidal endothelium. Although the molecules that play an important role in the development and function of TRM cells are not fully understood, several studies have defined the key Atty. Dkt. No.: 116639-2710 transcriptional regulators such as Hobit, Blimp-1, Runx3, Etv5, Id3, fatty acid binding proteins (FABPs)10,20-23, and cytokines such as interleukin (IL)-15 and transforming growth factor beta (TGF-β) that contribute to TRMcell development and maintenance4,24-26. Besides their protective role in infections, it is now well-appreciated that TRM cells also play a critical role in cancer immunosurveillance27,28. Several studies have shown a positive association between tumor TRMcells and favorable clinical outcome in patients with breast cancer29,30, cervical cancer31, esophageal cancer32, gastric cancer33, liver cancer34, head and neck cancer35, lung cancer36, melanoma37, and pancreatic cancer38. These results suggest that the abundance of TRMcells in the tumor tissue is a prognostic indicator for survival outcomes. Functional studies in murine tumor models have further confirmed the pivotal role of TRMcells in driving anti-tumor immune responses22,23. Thus, targets that modulate the magnitude and quality of TRM responses are likely to have a potential therapeutic role in certain infections and cancer types as well as in autoimmune diseases, where TRMcells play a pathogenic role39. Unbiased gene expression studies in humans and mice have discovered a number of gene transcripts that are highly enriched for their expression in TRM cells isolated from various tissues and tumor types10,20,22,23,25,30,35,36,40. However, the functional role of the molecules encoded by TRM-enriched gene transcripts is not well-defined. One such molecule is a poorly characterized G protein-coupled receptor (GPR), called GPR2541. GPRs are the largest superfamily of transmembrane receptors in the genome42, they interact with a large number of extracellular ligands43and transmit intracellular signals by activating heterotrimeric guanine nucleotide-binding proteins44. The structure and cellular localization of GPRs make them attractive targets for drug development45. Applicant’s recent transcriptomic study showed that GPR25 is expressed at significantly higher levels in TRMcells compared with non-TRMcells in the human lung and tumor tissues36. GPR25 has long been considered an orphan receptor with no known endogenous ligand. However, a recent study reported that C-X-C motif chemokine 17 (CXCL17), a chemokine expressed mainly by epithelial cells in the respiratory tract and non- intestinal mucosae tissue, functions as a ligand for GPR25 and mediates lymphocyte homing to these tissues46. Additionally, Gpr25 also has been reported to have a ligand-independent constitutive activity47. In this study, using genetic models, Applicant demonstrate that Gpr25 plays an important role in the development and function of TRMcells in the liver and lung. Atty. Dkt. No.: 116639-2710 Tissue-resident memory (TRM) CD8+T cells are key players that orchestrate protective anti-viral and anti-tumor immune responses1-3. The molecules that support their development and function are not fully defined. Here, Applicant report on the regulation and function of a G-protein coupled receptor, GPR25 that is expressed at high levels in TRM cells compared to non-TRM cells. TGF-β, a key cytokine involved in the development of TRM cells4, induces the expression of GPR25 in CD8+T cells, and SMAD1, a key transcription factor downstream of TGF-β signaling5, binds to TRM-associated cis-regulatory elements in the GPR25 locus. Adoptively transferred T cells from Gpr25-deficient mice showed no significant differences in their accumulation in the liver and lung of recipient mice after viral infection, but they exhibited impaired development into TRMcells. In a tumor challenge model, Gpr25- deficient memory T cells showed significantly reduced expansion and a diminished capacity to control lung metastasis compared to Gpr25-sufficient T cells. Single-cell transcriptomic analysis indicated that Gpr25 deficiency impacted the development of TRMcells with stem-like transcriptional features, including expression of TCF1, a key transcription factor promoting stemness in T cells6. Notably, following antigen re-challenge, Gpr25-deficient TRM cells displayed defects in their ability to differentiate into secondary TRMcells and maintain the TRMcell population. Gpr25-deficient T cells showed negative enrichment for TGF-β signature genes and impaired responses to TGF-β, indicating that Gpr25 enhances TGF-β signaling to promote the development of TRMcells. Applicant’s findings support the concept that modulating Gpr25 function may be an attractive therapeutic option to boost the magnitude and quality of TRMresponses generated in the context of infection and cancer. Example 2: GPR25 Antagonism in Tissue-resident memory T Cells TGF-β induces expression of GPR25 in CD8+T cells Applicant previously found that GPR25 expression was significantly increased in both lung and tumor-infiltrating CD8+TRM cells when compared to non-TRM cells36. Notably, the expression of GPR25 was strongly correlated with the expression of several key TRM-associated genes, such as ZNF683, RBPJ, ITGAE, ITGA1, S1PR1 and S1PR536. Because TGF-β is known to tightly regulate the expression of many TRM-associated genes4, we tested its role in regulating the expression of GPR25. TGF-β treatment resulted in rapid induction of GPR25 in primary human Atty. Dkt. No.: 116639-2710 CD8+T cells that were polyclonally activated in vitro by using anti-CD3 and ant-CD28 antibodies (FIG. 1A). To determine how TGF-β signaling regulates expression of GPR25, we analyzed assay for transposase-accessible chromatin using sequencing (ATAC-seq) profile of the GPR25 locus in human CD8+T cell subsets36,48. Three regions (C1, C2, C3) upstream of GPR25 transcription start site (TSS) displayed prominent transposase accessible peaks (ATAC-seq peaks) in tumor-infiltrating CD8+TRMcells compared to cell types not expressing GPR25 like non-TRMcells or circulating naïve CD8+T cells (FIG. 1B, top panel). The C2 region, however, displayed prominent transposase accessibility in activated CD8+T cells. Our analysis suggested that these three cis-regulatory regions are likely to be involved in the regulation of GPR25 with C1,2,3 regions associated with TRMcells and C2 region with T cell receptor (TCR) activation. Notably, analysis of ENCODE transcription factor ChIP-seq data49showed that C1, C2 and C3 cis-regulatory regions bind to nuclear factor of activated T-cells (NFAT) and Suppressor of Mothers Against Decapentaplegic (SMAD)1, key transcription factors downstream of TCR50and TGF-β signaling5, respectively, suggesting that expression of GPR25 is likely to be co-regulated by these signaling pathways (FIG. 1B, bottom panel). Applicant next assessed suitability of mouse models for testing the role of GPR25 in the development of TRMcells in vivo. First, we noted that GPR25 is highly conserved across species with 75% sequence homology with the murine ortholog (FIG. 7A). Second, similar to the observation in human T cells, Gpr25 expression was readily induced by TGF-β in murine CD8+T cells that were activated in vitro by cross-linking TCR and CD28, but its expression gradually declined over time (FIG. 1C). Third, in unmanipulated wildtype C57BL / 6 mice (> 90 days old), CD8+T cells in a non-lymphoid organs such as small intestinal intra-epithelial lymphocytes (siIEL) and liver, especially those expressing the TRMmarker CD6910,15,20, expressed higher levels of Gpr25 transcripts when compared to splenic CD8+T cells, which comprise mainly of circulating naïve and central memory T cells (TCM cells) (FIG. 1D and FIG. 7B). Thus, in both mice and humans, GPR25 is a TGF-β inducible gene that is selectively expressed in TRM cells. Gpr25 promotes development of liver TRMcells. To investigate the role of Gpr25 in the development of TRMcells, we utilized the Atty. Dkt. No.: 116639-2710 well-established mouse model of acute infection with lymphocytic choriomeningitis virus (LCMV)-Armstrong-OVA that is reported to induce CD8+TRM cells in multiple tissues, such as liver, kidney and intestine, as well as circulating CD8+effector memory (TEM) and central memory (TCM) T cells in the lymphoid tissues9,10,17,22. By breeding CD45.1.2 Gpr25+ / +(Gpr25 wild-type, WT) mice and CD45.2 Gpr25- / -(Gpr25 knock out, KO) mice with OT-I TCR transgenic mice, which express the transgenic T cell receptor (TCR) specific to SIINFEKL peptide of ovalbumin (OVA)51, we generated mice with congenically marked Gpr25-sufficient (Gpr25+ / +) and Gpr25-deficient (Gpr25- / -) OT-I CD8+T cells (see Methods). Importantly, adoptive transfer of these congenically distinct OT-I T cells into CD45.1 recipient mice before infection with LCMV-OVA intraperitoneally (i.p.) allowed us to track the development of antigen (OVA)-specific memory T cell subsets in various tissues52. In this model, we first confirmed that TRM cells (CD45.1.2+CD62L−CD69+T cells in the liver) generated from the adoptively transferred OT-I CD8+T cells expressed higher levels of Gpr25 transcripts when compared to OT-I TCM and TEM cells (CD45.1.2+CD62L+CD69- and CD45.1.2+CD62L−CD69−T cells in the spleen, respectively) (FIGS. 8A – 8C). Consistent with their tissue-resident properties, TRMcells expressed significantly lower levels of transcripts encoding for sphigosine- 1-phosphate receptor (S1PR1), which promotes egress of T cells from tissue compartments53(FIG. 8C, right panel). To assess the relative role of Gpr25 in the development in TRMcells, we co- transferred equal numbers of congenically distinct Gpr25+ / +OT-I (WT) and Gpr25- / -OT-I (KO) CD8+T cells into CD45.1 recipient mice before infection with LCMV-OVA (i.p.) and then 90 days post-infection (dpi) compared the frequencies and memory phenotypes of transferred T cells in the spleen, liver and small intestine intraepithelial lymphocyte compartment (siIEL) (FIG. 2A and FIG. 8D). We found relatively equal proportions of Gpr25+ / +and Gpr25- / -OT-I T cells in the spleen, liver and siIEL (FIG. 2B), which suggested that the Gpr25 deficiency did not influence the accumulation of T cells in these tissue compartments. Further, Gpr25 deficiency also did not impact the memory phenotypes of transferred T cells in the spleen (FIG. 8E), a tissue compartment that is largely devoid of TRM cells. However, in the liver, the frequency of Gpr25- / -TRMcells, marked by CD69 expression, was significantly reduced when compared to Gpr25+ / +TRMcells, indicating a potential defect in the development of TRMcells (mean 27% versus 17%; FIG. 8E). The liver TRM cells (CD69+), as expected, co-expressed CXCR615,20, but Atty. Dkt. No.: 116639-2710 lacked expression of CD103 (FIG. 2C), a TRM marker for cells localized in the epithelial compartment10,15,20, and KLRG1 (FIG. 8E), a marker of effector memory T cells54, as reported previously15,20. Another notable finding was that the frequency of TRMcells in the siIEL compartment was not significantly different between Gpr25+ / +and Gpr25- / -OT-I T cells (FIG. 2C and FIG. 8E), which suggested that Gpr25 is dispensable for the development of TRM cells in the siIEL compartment. Applicant next performed parabiosis experiments to assess the residency potential of Gpr25+ / +and Gpr25- / -liver TRM cells. TRM cells were generated in vivo by transferring equal numbers of congenically distinct Gpr25+ / +OT-I (WT) and Gpr25- / -OT-I (KO) T cells into CD45.1 recipient mice (host) before infection with LCMV-OVA. To specifically assess the residency potential of TRM cells generated in this model, circulatory OT-I cells were first depleted by administrating anti-Gr-1 antibody2530 days post infection and then host mice were conjoined with naïve CD8KO mice (parabiont recipient) that lack CD8+T cells (FIG.2D). Thirty days post-parabiosis, Gpr25+ / +and Gpr25- / -OT-I T cells accumulated in equal proportions in the host liver (FIG. 2E). However, in the spleen of CD8KO parabiont recipient mice, Applicant observed a significantly higher proportion of Gpr25- / -OT-I (CD45.2) cells to Gpr25+ / +OT-I (CD45.1.2) cells (FIG. 2E). This finding suggested that Gpr25-deficient TRMcells had lesser tissue-resident potential i.e., were able to enter the circulation of parabiont recipient mice, when compared to Gpr25-sufficient TRMcells. Together, these results demonstrate that Gpr25 supported the development of liver TRMcells. Gpr25 deficiency impairs early stages of TRMcell development Studies have shown that the first wave of effector T cells entering tissue compartments can bear features of TRMcells54, and over time, in response to tissue-derived signals like TGF-β, these cells develop into established TRM cells. To assess if Gpr25 is impacting the early stages of TRM cell development, Applicant compared the phenotype of adoptively co-transferred Gpr25+ / +and Gpr25- / -OT-I CD8+T cells in the liver at earlier time points following LCMV-OVA infection (FIG. 3A). In the first 48 hours after infection, Applicant found no differences in the frequency, activation and proliferation status of transferred Gpr25+ / +versus Gpr25- / -OT-I T cells in the liver (FIG. 3B and FIGS. 9A – 9C). Even 5 days Atty. Dkt. No.: 116639-2710 post infection, Gpr25 deficiency had no measurable impact on either the frequency or phenotype (KLRG1+effectors) of transferred OT-I cells in the liver (FIG. 3C). Also at day 5, very few transferred OT-I T cells co-expressed the liver TRMmarkers CD69 and CXCR6; however, by day 12, Applicant could see a distinct population of CD69+CXCR6+OT-I T cells specifically in the liver but not spleen, which indicated that this population represented potential TRM precursor cells (FIGS.3C – 3E). Notably, Gpr25 deficiency resulted in a reduction of the frequency of these cells and a corresponding increase in KLRG1+effectors cells (FIG. 3C). Applicant found relatively equal proportions of Gpr25+ / +and Gpr25- / -OT-I T cells in the liver on days 5, 12, and 30 post infection (FIG. 3D), suggesting that Gpr25 has no impact on the accumulation and development of memory OT-I cells. By day 30, when the infection is cleared and memory responses are well-established55,56, the effects of Gpr25 on the formation of TRM cells (CD69+CXCR6+cells) and effector memory T cells (CD69−KLRG1+cells) were maintained (FIG. 3E). These CD69+T cells expressed the memory marker CD44, were IL7R+KLRG1−, markers of memory precursor cells56, and lacked expression of the TCM marker CD62L, confirming that this population represented bona fide TRM cells (FIG. 9D). Together, these results suggested that Gpr25 supports the differentiation of TRMcells over effector memory T cells even during the early stages of memory T cell development. Gpr25 supports the generation of stem-like TRM cells Applicant next asked if TRMcells that develop from Gpr25-deficient OT-I T cells exhibit qualitative differences when compared to those that develop from Gpr25-sufficient OT-I T cells. Differential gene expression analysis revealed marked differences in transcriptional profiles between Gpr25+ / +and Gpr25- / -TRMcells isolated from the liver of recipient mice 30 days post LCMV infection (FIG. 3A, FIG. 4A, FIG. 10A and Table 1). Applicant found that Gpr25+ / +TRM cells displayed significant positive enrichment of gene signatures linked to stem- like T cells compared to Gpr25- / -TRMcells (FIG. 4B and Table 3), while also displaying negative enrichment for gene signatures linked to effector cells. Notably, Gpr25+ / +TRMcells expressed lower levels of transcripts encoding for cytotoxicity-related effector cell molecules like granzyme B, granzyme K and perforin, and higher levels of transcripts encoding for transcription factors like T cell factor 1 (Tcf1, encoded by Tcf7) and lymphoid enhancer-binding factor 1 (Lef1) (FIG. 10A), which have been shown to play important roles in the initiation and Atty. Dkt. No.: 116639-2710 maintenance of stem-like and self-renewal potential of memory T cells as well as restraining their effector differentiation57-59. Applicant confirmed by real-time quantitative polymerase chain reaction (qPCR) and intracellular staining that TCF1 encoding transcripts and TCF1 protein levels are higher in Gpr25+ / +compared to Gpr25- / -liver TRM cells (FIG. 4C, FIG. 4D). Interestingly, as early as 12 days post LCMV infection, transferred Gpr25+ / +OT-1 T cells in the liver of recipient mice were significantly enriched for stem-like T cell gene signatures (FIG. 10B and Table 3), indicating that Gpr25 is likely to promote a stem-like program in the early stages of memory T cell development. Because Gpr25- / -TRMcells display defects in the generation of stem-like TCF1- expressing cells, Applicant hypothesized that following secondary infection, Gpr25- / -TRMcells are likely to show defects in the generation of secondary TRM cell population i.e., maintenance of TRM pool following re-infection. Given the capacity of adoptively transferred TRM cells, including liver TRMcells, to migrate and form secondary TRMcells at the same tissue of origin after re-infection15,23,60,61, Applicant utilized this secondary transfer approach to test whether Gpr25 deficiency impacted the generation of secondary TRM cells in the liver. To this end, Applicant performed secondary co-transfer of congenically distinct Gpr25+ / +and Gpr25- / -liver TRMcells, generated as described in the LCMV-OVA-induced TRMmodel (FIG. 3A), into CD45.1 naïve recipient mice before infection with LCMV-OVA (i.p.) (FIG. 4E). Thirty days after infection, Applicant found relatively equal numbers of transferred Gpr25+ / +and Gpr25- / -OT-I T cells in the liver (FIG. 4F), indicating no major defects in the ability of Gpr25-deficient TRM cells to migrate and generate memory T cells in the liver. However, the frequency of Gpr25- deficient TRMcells that differentiate into secondary TRMcells (CD69+CXCR6+) in the liver was significantly reduced when compared to Gpr25-sufficient TRMcells (FIG. 4G), while the frequency of secondary TEM cells (KLRG1+CD62L−CD69−) was increased (FIG. 4H and FIG. 10C). These results indicate that Gpr25-deficient TRM cells display defects in their ability to differentiate into secondary TRMcells following antigen re-challenge. Thus, by supporting the generation of TCF1-expressing TRM cells with stem-like features, Gpr25 is likely to play an important role not only in the development of primary TRM cells but also in the generation of secondary TRMcell population in the liver. Atty. Dkt. No.: 116639-2710 Gpr25 enhances T cell responses to TGF-β To assess how Gpr25 may influence the generation of stem-like TRMcells, Applicant focused on TGF-β signaling, which it is known to play an important role both in the generation of TRM cells62-67and the maintenance of TCF1-dependent stem-like program in CD8+memory T cells68. Notably, Applicant found a significant positive enrichment of TGF-β signature genes in Gpr25+ / +TRMcells compared to Gpr25- / -TRMcells in the liver of recipient mice (FIG. 4I). This pattern was evident in Gpr25+ / +T cells even during the early stages of infection (FIG. 10D; day 12 post infection). Thus, Applicant’s analysis of the transcriptomes of TRM cells suggested that Gpr25 may influence their responsiveness to TGF-β. To test this hypothesis, Applicant stimulated primary CD8+T cells in vitro with TGF-β for 24 hours and examined the phosphorylation status of SMAD proteins, which are the canonical transcriptions down-stream of TGF-β signaling69-71. As expected, Applicant found significantly lower expression levels of phosphorylated SMAD2 and SMAD3 proteins (pSMAD2 / SMAD3) in Gpr25- / -CD8+T cells compared to Gpr25+ / +cells (FIG. 4J). In addition, Applicant found that CD8+T cells overexpressing Gpr25 showed higher levels of pSMAD2 / SMAD3 when compared to T cells expressing the empty vector (FIG. 4K). Together, these finding supported the hypothesis that Gpr25 likely amplifies TGF-β signaling to influence the development of stem-like TRM cells. Gpr25 promotes development of lung TRMcells Given that GPR25 expression was selectively higher in human lung TRMcells compared to non-TRM cells36, Applicant utilized the LCMV-OVA infection model to ask if Gpr25 played an important role in the generation of lung TRM cells (FIG.11A). Applicant found equal proportions of adoptively transferred Gpr25+ / +and Gpr25- / -OT-I T cells in the lungs at day 30 and day 120 following infection with LMCV-OVA delivered intra-peritoneally (FIG. 11B). However, unlike the findings in small intestine intraepithelial lymphocytes (siIELs) (FIG. 2A), only a very small fraction of transferred OT-I cells co-expressed the canonical lung TRMmarkers CD69 and CD103 (FIG. 11C). Therefore, to induce the generation of a larger pool of CD69+CD103+lung TRM cells, Applicant utilized the intratracheal (i.t.) route for both co- transferring OT-I T cells (Gpr25+ / +and Gpr25- / -) and infecting the naïve CD45.1 recipient mice with LCMV-OVA22,72-74(FIG. 5A). Relatively equal proportions of Gpr25+ / +and Gpr25- / -OT-I T cells were seen in the lungs (FIG.5B). Thirty days after infection, Applicant were able to Atty. Dkt. No.: 116639-2710 detect a distinct population of CD69+CD103+OT-I TRM cells in the lungs (FIG. 5C). Notably, the ability of Gpr25-deficient OT-I T cells to develop into CD69+CD103+TRM cells in the lungs was significantly reduced when compared to Gpr25-sufficient OT-I T cells (FIG. 5C and FIG. 11D). To gain further insights into the mechanisms that may explain how Gpr25 promotes the development of CD69+CD103+TRMcells in the lungs, Applicant performed single- cell transcriptome analysis of Gpr25+ / +and Gpr25- / -OT-I memory T cells that were isolated from lung tissue 30 days after LCMV-OVA infection (i.t.) (see Methods). Based on transcriptomic features, OT-I T cells clustered into two major subsets; notably, a greater fraction of Gpr25+ / +versus Gpr25- / -OT-I memory T cells (62% versus 38%) were observed in cluster 0 (FIG. 5D). Similar to our findings in liver TRM cells (FIG. 4A, FIG. 4B), compared to cluster 1, cluster 0 cells, which were enriched for Gpr25+ / +T cells, expressed lower levels of transcripts encoding for molecules linked to effector properties like perforin, granzyme B, granzyme A, and higher levels of transcripts encoding for molecules linked to stem-like properties such as TCF1 and IL7R (FIG. 5E, FIG. 5F, FIG. 11E and ), This finding suggested that, similar to Applicant’s findings in the liver tissue, Gpr25 is likely to promote the development stem-like TCF-1-expressing T cells as opposed to effector T cells. To validate this finding, Applicant adoptively transferred Gpr25+ / +and Gpr25- / -OT-I T cells into separate cohorts of CD8KO recipient mice and then infected them with LCMV-OVA (i.t.) (FIG. 5G). As expected, Applicant found that the frequency of TCF1-expressing CD8+T cells in the lungs was significantly lesser in transferred Gpr25- / -OT-I T cells compared to Gpr25+ / +OT-I T cells (FIG. 5H). Applicant’s transcriptomic analysis also showed that T cells in cluster 0, which were enriched for Gpr25+ / +T cells when compared to cluster 1, displayed lower expression of transcripts encoding for the transcription factors ZEB2 and S1PR5, a sphingone-1-phosphate receptor that promotes egress of cells from tissues75(FIG. 5E, FIG. 5F and ). A recent study reported that the robust generation of TRM cells required TGF-β induced down-regulation of the transcription factor ZEB2 and its target gene S1PR513, which in turn promoted the sequestration of cells in the tissues. Taken together, it is tempting to speculate that Gpr25 may also play a role Atty. Dkt. No.: 116639-2710 in the downregulation of ZEB2-S1PR5 axis, potentially by modulating TGF-β signaling and thus favoring the generation of TRM cells in the lungs. Gpr25-deficient T cells fail to control lung metastasis. To determine if Gpr25-deficient OT-I memory T cells in the lungs display any functional impairment, we examined their capacity to control the growth of lung metastases in a model of secondary challenge with OVA-expressing B16F10 melanoma (B16F10-OVA) cells. We first verified that transferred OT-I memory T cells (OT-1 transfer), generated as previously described in FIG. 5A, provide better control of lung metastasis when compared to endogenous anti-tumor responses in mice that did not receive OT-I cells (no OT-1 transfer group) (FIG. 12A, FIG. 12B). In addition, to minimize the contribution of circulating T cells to the control of metastasis, Applicant administered FTY720, a sphingosine-1-phosphate receptor antagonist that blocks egress of cells from lymph nodes76, thus allowing us to primarily assess the functional role of T cells resident in the lungs (FIG. 12A). Mice that received FTY720 treatment developed more metastatic nodulus compared to mice that that did not receive FTY720 treatments, highlighting the relative contribution of circulating T cells to control of lung metastasis (FIG. 12B). More importantly, mice that received FTY720 treatment developed lesser number of metastatic nodules compared to cohorts of mice that did not receive OT-1 T cells, which suggested that lung memory T cells per se can provide control of metastasis independent of replenishment from circulating T cells (FIG. 12B, FIG. 12C). To assess if Gpr25-deficient memory T cells display impaired secondary lung T cell responses in the tumor challenge model, we co-transferred equal numbers of congenically distinct Gpr25+ / +and Gpr25- / -OT-I CD8+T cells prior to i.t. infection with LCMV-OVA, waited for 30 days to allow for the generation of memory OT-I T cells in the lungs as described in FIG. 5A, and then challenged the recipient mice with B16F10-OVA tumor cells i.v. to induce metastasis (FIG. 6A). Thirteen days after tumor inoculation, Applicant found that the frequency of Gpr25-sufficient OT-I cells in the lungs was significantly higher when compared to Gpr25- deficient OT-I cells (FIG. 6B), indicating a competitive advantage for Gpr25-sufficient OT-I memory T cells to expand following secondary antigen (OVA) challenge with OVA-expressing Atty. Dkt. No.: 116639-2710 tumor cells that metastasize to the lungs. Based on this finding, we hypothesized that Gpr25- sufficient OT-I memory T cells are likely to possess greater capacity to control lung metastasis. To test this hypothesis, two independent cohorts of CD45.1 wildtype (FIG. 6C) recipient mice received either Gpr25+ / +OT-I or Gpr25- / -OT-I CD8+T cells prior to i.t. infection with LCMV-OVA, then 30 days after infection, mice were challenged i.v. with B16F10-OVA cells and assessed for degree of lung metastasis following FTY720 treatment. Applicant found that the number of metastatic nodules was significantly lower in mice that received Gpr25- sufficient OT-I T cells when compared to those that received Gpr25-deficient OT-I cells (FIG. 6D). To exclude the contribution of host CD8+T cells, Applicant utilized CD8KO mice as recipients and tested the effects of Gpr25+ / +OT-I or Gpr25- / -OT-I CD8+T cells in controlling lung metastasis (FIG. 6E). As controls, cohorts of CD8KO mice that did not receive T cells were also included to specifically assess the contribution of transferred OT-I T cells on outcomes. As expected, Applicant found that CD8KO mice receiving Gpr25-deficient OT-I cells had poor survival outcomes, with nearly 50% death rate, while most CD8KO mice receiving Gpr25- sufficient OT-I cells survived at the time of analysis (FIG. 6F). Additionally, the number of metastatic nodules was significantly lower in CD8KO mice that received Gpr25-sufficient OT-I T cells when compared to those that received Gpr25-deficient OT-I cells or had no transfer of OT-1 T cells (FIG. 6G). Overall, our results suggest that Gpr25 is likely to have an important T cell-intrinsic role in the control of anti-tumor immune responses in a lung metastasis model. In Applicant’s previous transcriptomic survey36, GPR25 emerged as one of the top differentially expressed genes in the lung and tumor-infiltrating CD8+TRM cells when compared to non-TRMcells. In this study, Applicant shows that GPR25 expression is induced in CD8+T cells by TGF-β signaling. Because three TRM-associated cis-regulatory regions in the GPR25 locus can bind to SMAD1, the key transcription factor downstream of TGF-β signaling, Applicant proposes that GPR25 is likely to be a direct target gene of TGF-β. In an LCMV infection model, Applicant demonstrates that Gpr25 plays a key role in supporting the development of TCF1-expressing stem-like TRM cells in liver and lungs but not those that develop in the siIEL compartment. Future studies using other tissue-specific models of TRM generation can be utilized to examine the role of Gpr25 in tissue compartments like the skin, colon, upper airways and female reproductive tract. By using a lung metastasis model, Applicant Atty. Dkt. No.: 116639-2710 highlight the T cell-intrinsic role of Gpr25 in anti-tumor immunity by supporting TRM responses. Given the importance of TRM cells in anti-tumor immune responses, Applicant reasons that approaches to modulate TRMresponses by targeting the activity of GPR25 may hold promise in relevant clinical settings. Applicant’s single-cell transcriptomic analysis of Gpr25-sufficient and Gpr25- deficient memory T cells provided several mechanistic insights. Notably, Gpr25-sufficient TRMcells were enriched for molecules that promote a stem-like memory program, whereas Gpr25- deficient TRM cells were enriched for molecules linked to an effector program. These results provide an interesting insight, suggesting potential heterogeneity within TRMcell population with some TRMcells exhibiting more stem-like features, including expression of TCF1, that may contribute to the maintenance of the TRM cell pool and enabling rapid re-expansion upon antigen re-challenge. Applicant’s results suggest that Gpr25 supports the generation of TCF1-expressing TRMcells, i.e., a stem-like differentiation program while limiting the effector differentiation of TRM cells by augmenting TGF-β signaling68. Furthermore, Applicant’s analysis revealed that Gpr25-deficient memory T cells also displayed defects in downregulating the ZEB2-S1PR5 axis that is required for preventing T cell egress from tissues. This finding suggested that Gpr25 signaling is likely to enhance tissue retention of TRMcells, a notion that is supported by Applicant’s parabiosis studies. Based on recently published data that TGF-β signaling is essential for the maintenance of both the TCF1-dependent stem-like program in CD8+memory T cells68as well as for the down-regulation of ZEB2-S1PR5 axis to promote tissue retention13, Applicant’s findings suggest that Gpr25 mediates its effects on TRM development and maintenance by either directly or indirectly modulating TGF-β signaling. Finally, although GPR25 has been shown to have constitutive activity without ligand engagement41,47, identification of the endogenous ligand is likely to shed light on endogenous signals that modulate GPR25 activity in T cells. A recent study identified a chemoattractant chemokine CXCL17 as the ligand for GPR25, and reported that CXCL17- GPR25 functions as a chemoaffinity axis that mediates lymphocytes homing to lung, non- intestinal mucosa and CNS46. Applicant’s study highlights that Gpr25 has important non- chemotactic functions and supports the generation and maintenance of TRMcells in the liver and lung. Further functional studies under physiological conditions and employing genetic knock-out Atty. Dkt. No.: 116639-2710 models (Gpr25-deficient mice) are likely to clarify the relative contribution of the chemotactic versus non-chemotactic function of Gpr25 in mediating protective immunity in infections and cancer. Discussion Applicant’s single-cell transcriptomic analysis of Gpr25-sufficient and Gpr25- deficient memory T cells provided several mechanistic insights. Notably, Gpr25-sufficient TRMcells were enriched for molecules that promote a stem-like memory program, whereas Gpr25- deficient TRM cells were enriched for molecules linked to an effector program, which suggests that Gpr25 is likely to support a stem-like differentiation program whilst restraining the effector differentiation of TRMcells. Gpr25-deficient memory T cells also displayed defects in downregulating the ZEB2-S1PR5 axis that is required for preventing egress of T cells from the tissues, suggesting that Gpr25 signaling is likely to enhance tissue retention of TRM cells. Based on recently published data that TGF-β signaling is essential for the maintenance of both Tcf-1- dependent stem-like program in CD8+memory T cells as well as for the down-regulation of ZEB2-S1PR5 axis to promote tissue retention9, Applicant hypothesizes that Gpr25 may mediate its effects on TRMdevelopment by either directly or indirectly modulating TGF-β signaling, which should be tested in future studies. Finally, although GPR25 is an orphan receptor and has been shown to have a constitutive activity without ligand engagement38,43, identification of the endogenous ligand is likely to shed light on endogenous signals that modulate GPR25 activity in T cells. Two potential ligands, Apelin and Apela, are known to activate GPR25 and decrease intracellular cAMP levels in non-mammalian vertebrates66, however, their function in human T cells is not known. Future studies to identify physiological ligand(s) that selectively modulate GPR25 signaling in humans and mice are likely to facilitate the development of therapies that target the GPR25 signaling pathway for controlling TRM responses in health and disease. Methods Mice. Gpr25 germline deletion mice (Gpr25- / -; RRID:MMRRC_047952-UCD) were generated by the Knock out Mouse Project (KOMP) and obtained from Mutant Mouse Resource and Resource Centers (MMRRC). Briefly, CRISPR guide(s) targeting of Gpr25 exon and Cas9 protein were microinjected or electroporated into C57BL / 6N zygotes to generate the Atty. Dkt. No.: 116639-2710 Gpr25em2(IMPC)Bayallele (Gpr25- / -) and progeny were screened for the desired mutation. Gpr25- / -mice were viable, and were crossed with OT-I mice51, which express the transgenic TCR recognizing the OVA-specific class 1 epitope OVA257-264, to generate mice with Gpr25-deficient OT-I cells. OT-I mice (stock no.003831), CD45.2 C57BL / 6J mice (stock no.000664), CD45.1 mice (B6.SJL-PrprcaPepcb / BoyJ, stock no. 002014) and CD8aKO mice (B6.129S2- Cd8atm1Mak / J, stock no. 002665) were obtained from The Jackson Laboratory. Mice were maintained in specific-pathogen-free conditions in accordance with the Institutional Animal Care and Use Committees (IACUC) of the La Jolla Institute for Immunology (LJI). All mice were maintained on a C57BL / 6 background and under a standard 12-hour light / 12-hour dark cycle. Mice were fed standard rodent chow and water ad libitum. Age- (8-12 weeks old) and sex- matched mice (female and male) were used in all experiments. All procedures were approved by the La Jolla Institute for Immunology Animal Ethics Committee. Infection model and adoptive T cell transfer. Lymphocytic choriomeningitis virus Armstrong strain (LCMV) expressing OVA (LCMV-OVA) was a gift from Ananda Goldrath (University of California, San Diego, CA) and generated by Juan-Carlos de la Torre (The Scripps Research Institute, La Jolla, CA)77. For co-transfer experiments, congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were mixed in a 1:1 ratio and 1 x 106total cells were adoptively co-transferred intravenously into CD45.1 recipient mice. Mice were then infected with 2 x 105plaque-forming units (PFU) of LCMV- OVA by intraperitoneal (i.p.) and memory T cell responses analyzed at indicated time points. For the secondary TRM generation model, congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I TRMcells, generated in the liver 30 days after the LCMV-OVA infection model (CD69+CD62L−OT-I CD8+T cells), were isolated from liver and adoptively transferred at a 1:1 ratio (5 x 103total cells) into CD45.1 naïve recipient mice before infection with 2 x 105PFU LCMV-OVA (i.p.). To enhance generation of TRM cells in lung tissue, congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were mixed in a 1:1 ratio and 1 x 106total cells were adoptively co-transferred intratracheally into CD45.1 recipient mice before infection with 5 x 104PFU of LCMV-OVA delivered intratracheally. Parabiosis Surgery. Mice were matched with body weight and body size, and co- housed for 2 weeks before experiments. For the surgery, mice were anesthetized with isoflurane, Atty. Dkt. No.: 116639-2710 and flank hair was removed. A skin incision of approximately 0.5 cm was made above the elbow to 0.5 cm below the knee joint in both animals. Mice were joined at the knees and elbows with 3.0 silk suture, connecting chest and inguinal adipose tissue with 6.0 PGA absorbable suture. Then the skin was joined with continuous sutures with 3.0 nylon suture. Parabiotic pairs were analyzed 30 days after surgeries. Mouse tissue processing and cell isolation. Liver tissue samples were cut into small pieces, passed through 70 µM cell strainers (Miltenyi Biotec) twice, and then resuspended at room temperature (RT) in red blood cell (RBC) lysis buffer (Cat. No. 420301, BioLegend) for 3-5 min depending on cell number before further analysis. Spleens were processed into single- cell suspensions and resuspended in RBC lysis buffer to remove erythrocytes. Total CD8+T cells were isolated from spleen and liver single-cell suspensions to > 95% purity using a CD8+T cell negative selection kit (Stem Cell Technologies). For isolation of CD8+T cells from small intestinal epithelium, Peyer’s patches were first removed, and the intestinal tissue was cut longitudinally and washed of luminal contents. The tissue was then cut into 1-cm pieces and incubated in 25 ml of Hank’s balanced salt solution (HBSS) containing 25 mM HEPES, 1 mM DTT and 5mM EDTA in a shaker at 200 rpm for 20 min at 37˚C. Cells in the supernatant were collected and passed through a 40 / 80% Percoll density gradient to enrich intraepithelial lymphocytes (siIEL). To isolate lymphocytes from lung tissues, lungs were well perfused with phosphate-buffered saline (PBS) and then cut into small pieces and dispersed for 15 min with 1 ml of digestion buffer (RPMI-1640 + 10% FBS, supplemented with 200 U / ml Type 2 Collagenase (Worthington) and 15 µg / ml DNase (Sigma)) while shaking at 37˚C. Flow cytometry. Single-cell suspensions were prepared and surface stained in fluorescence-activated cell sorting (FACS) buffer (PBS + 1.5% fetal bovine serum) for 20 minutes at 4˚C with the following antibodies (purchased from BioLegend): anti-CD8⍺ (53-6.7, Cat. No. 100747); anti-CD8β (YTS156.7.7, Cat. No. 126613); anti-CD45.1 (A20, Cat. No. 110730); anti-CD45.2 (104, Cat. No. 109822); anti-CD69 (H1.2F3, Cat. No. 104506); anti- CD103 (2E7, Cat. No. 121422); anti-CXCR6 (SA051D1, Cat. No. 151111); anti-KLRG1 (2F1 / KLRG1, Cat. No. 138414); anti-CD62L (MEL-14, Cat. No. 104408); anti-CD44 (IM7, Cat. No. 103059); anti-CD127 (A7R34, Cat. No. 135012); anti-PD-1 (29F.1A12, Cat. No. 135220). For intracellular staining, cells were fixed and permeabilized with the “Foxp3 staining buffer set” Atty. Dkt. No.: 116639-2710 (Cat. No. 00-5523, eBioscience), following the manufacturer’s protocol, and then stained with anti-granzyme B (QA16A02, Cat. No. 372208, BioLegend). For phosphorylated protein staining, cells were fixed by “BD Phosflow Lyse / Fix buffer” (558049, BD) at 37˚C in the dark for 10 minutes. Then the cells were permeabilized with 90% methanol at 4˚C for 30 minutes, and then stained with anti-Smad2(pS465 / pS467) / Smad39pS423 / pS425) (562586, BD). For flow cytometric analysis samples were acquired on LSRFortessa (BD Biosciences) or an LSRII flow cytometer (BD Biosciences) and then analyzed using FlowJo version 10.5.3 (Tree Star). Isotype controls for each of antibodies were used for separating negative and positive populations and all gates to define cell subsets were based on this method. For cell sorting experiments, all samples were sorted on a BD FACS Fusion system or acquired on a BD FACS Fortessa system (BD Biosciences). In vitro T cell activation assays. Using the “Naïve CD8+T cell Isolation Kit” (Cat. No. 130-093-244, Miltenyi Biotec) naïve human CD8+T cells were isolated from peripheral blood mononuclear cells, obtained from blood samples of de-identified donors from the San Diego Blood Bank (SDBB). Subsequently, the naïve CD8+T cells (0.3 x 106per well) were stimulated in a 48-well plate pre-coated with anti-CD3 (1 µg / mL, Cat. No. 16-0037-85, eBioscience) and anti-CD28 (1 µg / mL, Cat. No. 16-0289-85, eBioscience) in the presence or absence of recombinant human TGF-β (20 ng / mL, Cat. No. 240-B, R&D Systems) for 24 hours and 48 hours. Naïve mouse CD8+T cells (CD8+CD44loCD62Lhi) were isolated from the spleen, and 0.5 x 106cells were stimulated in a 48-well plate pre-coated with anti-CD3 (1 µg / mL, Cat. No. BE0001-1, BioXCell) and anti-CD28 (1 µg / mL, Cat. No. 16-0281-85, eBioscience) in RPMI-1640 medium supplemented with 10% FBS and TGF-β (10 ng / mL, Cat. No. 763102, BioLegend) or mouse IL-15 / IL-15R complex (0.4 ng / mL, Cat. No. 50-898-0, Invitrogen) for 24 hours and 48 hours or the indicated time points. In vivo T cell proliferation assay. Naïve OT-I CD8+T cells (CD8+CD44loCD62Lhi) were purified to > 95% purity from pooled spleens of Gpr25 WT and Gpr25 KO mice using naïve CD8+T cell negative selection kit (Stem Cell Technologies). The cells were labelled with 5 µM Cell Trace Violet (CTV, Cat. No. C34557, Invitrogen) in pre- warmed PBS. Labelling was performed by incubating at 37˚C for 20 min, and the reaction stopped by adding five times the original staining volume of RPMI-1640 medium supplemented Atty. Dkt. No.: 116639-2710 with 10% FBS. The cells were incubated for at least 10 min to allow the CTV reagent to undergo acetate hydrolysis. CTV-labelled OT-I cells were then adoptively transferred to recipient mice before infection with 2 x 105PFU LCMV-OVA, and analyzed 24 hours and 48 hours after infection. qRT-PCR. Total RNA was extracted using TRIzol reagent (Cat. No. 10296-028, Invitrogen), after which 1.0 µg of total RNA was subjected to cDNA synthesis using a SuperScript Reverse Transcription System (Cat. No. 18080-051, Invitrogen). The expression levels of each gene were normalized to Hprt transcript levels. The mouse primer sequences used in the qRT-PCR were as follows: Hprt forward, 5’- CTGGTGAAAAGGACCTCTCGAAG-3’, Hprt reverse, 5’- CCAGTTTCACTAATGACACAAACG-3’, S1pr1 forward, 5'- GTGTAGACCCAGAGTCCTGCG-3', S1pr1 reverse, 5'- AGCTTTTCCTTGGCTGGAGAG-3', Gpr25 forward, 5'- TCACCCTGATCTGCTACTGG-3', Gpr25 reverse, 5'- CGCACTGCTATTGACGAAAGC-3'. The expression levels of human GPR25 were normalized to HPRT1 transcript levels. The human primer sequences used in the qRT-PCR were as follows: HPRT1 forward, 5’- ACCAGTCAACAGGGGACATAA-3’, HPRT1 reverse, 5’- CTTCGTGGGGTCCTTTTCACC-3’, GPR25 forward, 5’- CGCTCATCTACCTCCTGCTG-3’, GPR25 reverse, 5’- ACACGGAACTGTCGTCCCT-3’. Tumor model. OVA-expressing B16F10 (B16F10-OVA) cells were a gift from the J. Linden laboratory (LJI) and tested negatively for mycoplasma infection. Plasmocin (InvivoGen) was used as a routine addition to culture media to prevent mycoplasma contamination. For inducing experimental lung metastasis, 1 x 106B16F10-OVA cells were injected (i.v.) into either naïve mice or mice previously infected with LCMV-OVA. For FTY720 treatment, mice were intraperitoneally injected with FTY720 diluted in sterile PBS at 1mg / kg at indicated time points. Mice were sacrificed on day 14 after injection of tumor cells, and lung tissues were harvested and subjected to FACS analysis. Lung metastatic nodules present on the surface of the 5 lobes of the lungs per mouse were counted. Single-cell transcriptome assay and analysis. Single-cell transcriptome analysis was performed on cells from two experiments: (i) Liver dataset: we sorted and pooled Gpr25+ / +- / - + − (WT; CD45.1.2) and Gpr25 (KO; CD45.2) OT-I TRMcells (CD69 CD62L KLRG1−) C- Atty. Dkt. No.: 116639-2710 D8+T cells in the liver of recipient 8 mice at 30 days post LCMV infection. Prior to infection, congenically distinct Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells were co-transferred at a 1:1 ratio into CD45.1 recipient mice, (ii) Lung dataset: we sorted and pooled Gpr25+ / +(WT; CD45.1.2) and Gpr25- / -(KO; CD45.2) OT-I CD8+T cells isolated from lungs of 6 recipient mice at 30 days post infection. Sorted cells were processed using the 10x Genomics 3’ Tag v3.0 chemistry kit following manufacture’s instruction (10x Genomics), and sequenced on Illumina NovaSeq 6000 platform. The sequence data from each library were collapsed into Unique Molecular Identifier (UMI) counts by mapping the reads to the mm10 reference (v3.0.0) using the Cell Ranger (v3.1.0) software (10x Genomics) and aggregated as described78-80. Aggregated data was transferred to the R statistical environment for doublet exclusion and analysis using the Seurat software (v4.1.1)81, as described78-80. To further minimize doublets, we applied Scrublet software82(expected_dublet_rate = 0.06; v0.2.3) and included cells with a doublet score ≤ 0.3 for further analysis. Cells with low-quality transcriptomes and potential remaining doublets were excluded from further analyses based on these criteria: <300 and >5,000 unique genes, <200 and >30,000 total UMI content, and > 10% of mitochondrial UMIs for liver dataset; and <300 and >5,000 unique genes, <200 and >20,000 total UMI content, and > 10% of mitochondrial UMIs for lung dataset. Unbiased clustering analysis was performed using Seurat software (v4.1.1). A first round of clustering analysis was performed and single-cell transcriptomes not meeting quality control thresholds (see above) as well as clusters of contaminating cells characterized by low expression of Cd8b1 were eliminated from the second round of analysis. For both rounds of analysis, only genes expressed in at least 0.1% of the cells were included. Expression counts were then log-normalized and scaled (by a factor of 10,000) per cell. Variable genes were detected with the variance stabilizing transformation (VST) method and most variable genes (UMI mean >0.01) accounting for the top 25% of the total standardized variance were selected for downstream analysis. Transcriptomic data from each cell were scaled by regressing the following cell-specific variables: number of UMIs-detected, percentage of mitochondrial UMIs, and cell-cycle score. Principal component analysis (PCA) was performed, and the first 20 principal components (PCs) for both, liver and lung datasets were selected for downstream analysis based on the standard deviation of PCs. Cells were clustered using Seurat’s functions FindNeighbors and FindClusters with a resolution of 0.2 and 0.4 for the liver and lung datasets, Atty. Dkt. No.: 116639-2710 respectively. Pairwise single-cell differential gene expression analysis was performed using the R package MAST (v1.14.0)83with cellular detection rate (CDR) as a covariate, after normalizing the data to log2counts per million (log2(CPM+1)). A gene was considered as differentially expressed if its Benjamini-Hochberg adjusted P-value (called false discovery rate) was <0.05 and log2 fold change was >0.25. Cluster-specific markers were determined by MAST using the Seurat function FindAllMarkers with default parameters. Shape of violin plots represents the distribution of expression (based on a Gaussian Kernel density estimation model) of cells, including cells with no expression. Violin plots are colored according to the percentage of cells expressing the transcript of interest. UMAPs are colored according to the normalized transcript counts of the genes of interest. ATAC-seq data analysis. ATAC-seq data of resting and activated naïve CD8+T cells, TRM and non-TRM CD8+T cells were analyzed as described previously36,84using custom ATAC-seq data processing pipeline ATACproc (https: / / github.com / ay-lab / ATACProc). Briefly, single-end ATAC-seq reads were aligned to hg19 reference genome using Bowtie2 (version 2.3.3.1)85,86, with parameters “-k 4 --mm –threads 8 –X 2000”. We excluded the reads corresponding to mitochondrial genome and chromosome Y. Uniquely mapped reads with mapping quality ≥ 30 were retained using SAMtools (version 1.6)87. Duplicate reads were discarded by Picard tools MarkDuplicates routine (https: / / broadinstitute.github.io / picard). To account for the 9 bp distance between two adapters inserted by the Tn5 transposase88, we then shifted all the reads aligned to the positive (+) strand by +4 bp, and the reads aligned to the negative (-) strand by -5 bp, using deepTools’ “alignmentSieve" routine89. We also discarded reads overlapping with the blacklisted regions (provided in https: / / github.com / Boyle- Lab / Blacklist / tree / master / lists). Coverage tracks were normalized by scaling factor, bins per million mapped reads (BPM), using the “BamCoverage” routine from deepTools89using the arguments “--binSize 50 --normalizeUsing BPM --extendReads”. MACS2 (version 2.1.0)90was used for peak calling, with parameters: “-g hs –q 0.05 -- nomodel --nolambda --keep-dup all -- call-summits --shift -100 --extsize 200”. UCSC Genome Browser was used to display the tracks. Transcription factor (TF) ChIP-seq data analysis. TF ChIP-seq data for NFATC1, NFATC3 and SMAD1 for GM12878 cells were retrieved from the ENCODE database91. Briefly, reads were aligned using Bowtie2 (version 2.3.3.1)85,86to hg19 reference Atty. Dkt. No.: 116639-2710 genome, and coverage tracks were normalized by scaling factor, bins per million mapped reads (BPM), using the “BamCoverage” routine from deepTools89using the arguments “--binSize 10 -- normalizeUsing BPM --extendReads 200”. UCSC Genome Browser was used to display the tracks. Quantification and statistical analysis. Details regarding the number of samples or mice per group, replicates in independent experiments and statistical tests can be found in the figure legends. Sample sizes were based on published studies to ensure sufficient numbers of mice in each group for reliable statistical testing and accounting for variability. The sample sizes are indicated in the figure legends. Age- (8-12 weeks old) and sex-matched mice (female and male) were used in all experiments. For statistical analysis, all experiments, unless stated in figure legends, were performed at least three times independently. Statistical analyses were performed using GraphPad Prism 9 and the statistical tests employed are indicated in the figure legends. Example 3: HTS compatible GPR25 LIFT assay and develop secondary assays to enable a screening cascade to identify agonists. (i) Generation of a GPR25 LIFT cell line. Site-directed mutagenesis by PCR introduced genetic mutations that replaced tryptophan-164 in GPR25 with alanine (W164A). This mutation disrupts the highly conserved tryptophan residue residing in the fourth transmembrane domain. Similar mutations have been found to cause ER retention of other GPCRs108-110. Although these mutations may ultimately affect receptor function, in this assay they serve the sole purpose of facilitating ER retention of the target. The cDNA constructs encoding mutant GPR25(W164A) were subcloned into an expression vector that encodes a 42- amino acid portion of β-gal, the Pro-link (PK) fragment. Next, GPR25(W164A)-PK are transfected into the PathHunter® U2OS Endosomal-EA (Endo-EA) cells (DiscoverX). These cells express the remaining portion of the β-gal enzyme fused with the early endosomal protein EEA1. With β-gal split into two fragments: PK and EA, and separated within the cell, no functional β-gal is produced. When brought together, they form a functional enzyme capable of converting substrate to light (FIG. 13). Atty. Dkt. No.: 116639-2710 Stable pools of U2OS-Endo-EA cells expressing GPR25(W164A)-PK are tested for Enzyme Fragment Complementation (EFC) functionality and relative expression of the receptor. Cells are lysed and enzyme substrate together with excess exogenous EA or buffer (No- EA) is added. The excess EA exogenous forces complementation of the β-gal fragments independent of endogenous EA and serves two purposes: (i) to verify integrity and functionality of the reporter; (ii) to provide a relative level of PK-tagged receptor expression. Compared to EA-expressing parental U2OS cells (those lacking a PK-tagged receptor), cells expressing GPR25(W164A)-PK are expected to show high basal activity (no exogenous EA added). Activity increases with the addition of exogenous EA. This determines (i) the fraction of the receptor that migrates to the membrane despite the presence of the ER-retaining mutations, and, more importantly, (ii) the level of increased signal resulting from the addition of exogenous EA, which will demonstrate robust expression of GPR25. Applicant also assesses retention of GPR25(W164A)-PK in the ER using a monoclonal antibody targeting PK, and confocal microscopy. The use of the exogenous EA tag and PK antibody to test the integrity of the assay is an important aspect of applying this technology to understudied receptors, allowing for validation of receptor expression and intracellular localization without a receptor-specific antibody or positive control. (ii) Miniaturization of LIFT assay: Once stable clones are validated, the GPR25- LIFT assay is miniaturized for use in 1536 well plates. The optimal cell-seeding density, DMSO tolerance, and effect of FBS have already been determined for this assay platform from other screens. Positive control. To establish fully a cell-based assay for HTS, one must have a positive control to generate a high signal relative to a negative control or low signal. While this is easy for targets with known ligands like ADRB2, the lack of a known ligand for GPR25 presented a challenge to assay development. A basal level of receptor forward trafficking in the LIFT assay facilitates the use of the proteasome inhibitor bortezomib as a non-specific high-signal control compound. By blocking the cell’s endogenous system for degrading the mutant oGPCR bortezomib creates a “back-log” in the ER allowing some of the misfolded GPR25 protein to “leak” through. Assay parameters. Stable U2OS LIFT cells expressing the mutant target GPR25 are first dispensed at a range of cell seeding densities (500–1500 cells / well). Bortezomib (10µM) Atty. Dkt. No.: 116639-2710 is used induce trafficking of the mutant oGPCR and produce EFC-derived luminescence. Next, the effect of serum (0.0-10.0% FBS) and DMSO (0.0–2.0% final v / v) on assay performance is determined. The variability of the assay is determined by running triplicate max / mid / min plates on three days and then calculating the Z’ factor112. The minimal performance criteria (Z’ ≥ 0.5, S / N ≥ 2.0, %CV ≤ 10) is required for a HTS. (iii) Using the primary LIFT assay: To confirm the suitability of the primary pharmacochaperone assay developed, a pilot screen consisting of 3 plates (1,536 well) is screened in two independent experiments. Compounds are tested at both 10 and 20 µM final concentration to determine screen concentration and estimate hit rate. The pilot screen consists of library of pharmacologically active compounds (LOPAC), and 3 plates containing diverse chemicals from the SBP GPCR library. (iv) Develop secondary, orthogonal and counter assays: The mutant GPR25 used in the LIFT assay does not occur naturally, its only purpose is to retain the target in the ER, keeping PK separate from the EA until compounds induce forward trafficking (FIG.13). Hits from the primary LIFT assay are confirmed as active on native wild-type GPR25. The signaling of human GPR25 is unknown, but in non-mammalian system it is coupled to Gi-cAMP (activation of the receptor inhibits forskolin-stimulated cAMP production) and results in receptor internalization72. Equivalent assays to monitor these end points in HEK293 over-expressing human wt GPR25 have already been described and characterized72, and these assays are used to evaluate hits identified from the screen. Note, GPR25 CHO-K1 b-arrestin cell lines are commercially available. Applicant establishes the primary HTS assay based on the LIFT platform and develops downstream secondary assays to enable a hit ID testing funnel (FIG. 14). Example 4: GPR25 agonist lead generation and characterization for functional studies in vitro and in vivo. (i) Elaborate structure-activity relationship (SAR) by medicinal chemistry. To reveal nascent SAR, Applicant starts by purchasing compounds that differ from hits in select chemical groups, which are acquired from trusted commercial vendors. In cases where Applicant is unable to expand the hit set by purchase, Applicant directly begins the process of hit expansion Atty. Dkt. No.: 116639-2710 through initiating a classic Hit to Lead medicinal chemistry campaign. Applicant uses the panel of cell-based GPR25 assays to assess potency and selectivity with the goal of optimizing SAR for whole-cell activity. Hit prioritization and expansion efforts leverage the chemistry expertise of Dr. Patrick Kenny (Co-I), the lead medicinal chemist at SBP for the NIH-supported initiative to find chemical probes directed to 10 brain-expressed oGPCRs. Applicant focuses on analogs that show enhanced potency from the original hit, while retaining the same mechanism of action. Applicant performs multiple rounds of analysis of analogs for each hit, and based on this data, additional rounds of analogs are synthesized and tested to define the most critical functional groups responsible for evoking the biological effect at GPR25. After an initial hit expansion phase, Applicant synthesizes analogs at a rate of ~8-10 compounds per month, focused on advancing 2-3 scaffolds to lead status as depicted FIG. 15. (ii) Physiologically-relevant cell based assays. The primary assay that is used to drive SAR will be dose-response activity in the GPR25 cAMP TR FRET assay. Due to the homology with APLNR Applicant uses this receptor as a selectivity screen in the SAR campaign, all reagents have already been developed for this receptor at SBP116. As SAR develops and the potency (EC50) of compounds increases below the 1 uM threshold, compounds are evaluated in more physiologically-relevant cell assays. More specifically, Applicant conducts assays on human T cells treated with TGF- β, which induces GPR25 expression (FIG. 16), to monitor their effects on activation, proliferation, cytokine release, and their ability to enhance responses to TGF-b. (iii) Determine physicochemical and pharmacological properties for in vivo development. Leads identified in this effort are intended for probing receptor function in cellular systems and with further refinement use in vivo. To assess the drug-like properties of select compounds, Applicant uses a series of standard in vitro ADME / T and physicochemical profiling assays in place. Briefly, aqueous solubility data are determined at pH 7.4 with UV detection. Lipophilicity is determined using a high-throughput shake-flask method with octanol and water. The cLogD and polar surface area are calculated through the use of ChemAxon software. Metabolic stability in human- and mouse-liver microsomes is determined by incubating compounds in 1 mg / mL microsomes; the metabolites are quantitated using liquid chromatography / mass spectroscopy methods. Atty. Dkt. No.: 116639-2710 Cellular permeability is determined using a monolayer of MDCK1 cells. Applicant profiles ~25-35 compounds in these assays, and lead compounds with appropriate potency and in vitro ADME properties are dosed (IV / PO / IP) in mice to determine pharmacokinetics. (iv) Lead selection and characterization in vitro and in vivo. The overall testing funnel for identifying lead compound(s) is depicted in FIG. 15. Applicant uses all the data generated in the various assays in an ongoing fashion to guide the design of analogs and enhance / evolve the SAR. With each iteration of analog refinement the potency threshold becomes increasingly rigorous. The selection of analogs synthesized in exploring SAR is driven by potency in in vitro cell-based assays, as potency improves this is supplemented by evaluation in more physiologically-relevant T cells assays and increasing emphasis will be placed on developing drug-like properties. Applicant discovers 2-3 leads that are suitable for evaluating activity to enhance lung TRMcell generation in mouse models of viral infection, as described in FIG. 5A. Comparing effects of lead agonist by using Gpr25-sufficient and Gpr25-deficient T cells in vivo enables Applicant to differentiate the effects mediated via Gpr25. Because of high sequence homology, GPR25 agonists potently activate murine Gpr25. However, if potency is lower, humanized mouse models can be used to determine activity of GPR25 in vivo. Applicant completes lead generation efforts culminating in the identification of 1- 3 hGPR25 agonists for functional testing in vitro (human T cells) and in vivo (mouse models). Applicant performs comprehensive efficacy and toxicity studies in mouse models for further advancing the drug-development pathway towards clinical testing. Feasibility in an academic setting. Applicant has extensive experience in HTS and lead optimization of screening hits identified from oGPCR LIFT screens. All the in vitro ADME assays are conducted at SBP on a routine basis, testing dozens of compounds each week, Similarly, pharmacokinetic studies are performed in the Exploratory Pharmacology Core facility at SBP. Example 5: The role of TGF-β signaling in the regulation and function of GPR25 in TRM cells. Although Gpr25 plays a critical role in the development of TRM cells, the Atty. Dkt. No.: 116639-2710 mechanisms regulating its expression in T cells in not known. Applicant previously found that the expression of GPR25 was strongly correlated with the expression of several key TRM- associated genes, such as ZNF683 (Hobit), RBPJ, ITGAE (CD103), S1PR1 and S1PR533. Because TGF- β is known to tightly regulate the expression of many TRM-associated genes69, Applicant investigated its role in regulating the expression of GPR25. Applicant found that TGF-β treatment resulted in rapid induction of GPR25 in primary human CD8+ T cells that were polyclonally activated in vitro by using anti-CD3 and ant-CD28 antibodies (FIG. 1C). Gpr25 expression was also readily induced by TGF-β in murine CD8+ T cells (FIG. 1A). To determine how TGF- β signaling regulates expression of GPR25, Applicant analyzed assay for transposase-accessible chromatin using sequencing (ATAC-seq) profile of the GPR25 locus in human CD8+ T cell subsets33,117. Three regions (C1, C2, C3) upstream of GPR25 transcription start site (TSS) displayed prominent transposase accessible peaks (ATAC-seq peaks) in CD8+ TRM cells compared to cell types not expressing GPR25 like non-TRM cells or circulating naïve CD8+ T cells (FIG. 1B, top panel). The C2 region, however, displayed prominent transposase accessibility in activated CD8+ T cells. Applicant’s analysis suggested that these three cis-regulatory regions are likely to be involved in the regulation of GPR25 with C1,2,3 regions associated with TRM cells and C2 region with T cell receptor (TCR) activation. Notably, analysis of ENCODE transcription factor ChIP-seq data118 showed that C1, C2 and C3 cis-regulatory regions bind to nuclear factor of activated T-cells (NFAT) and Suppressor of Mothers Against Decapentaplegic (SMAD)1, key transcription factors downstream of TCR119 and TGF-βsignaling120, respectively, suggesting that expression of GPR25 is likely to be co-regulated by these pathways (FIG. 1B, bottom panel). TGF- β and NFAT Expression Regulation of GPR25. (i) ChIP-sequencing studies. Applicant performs SMAD and NFAT ChIP-seq in T cells. Applicant tests at least two different ChIP-seq grade antibodies for SMAD1 (Diagenode, #C15410274; ThermoFisher #701168), SMAD 2 / 3 (Cell Signaling Technology, #8685S; Abcam, ab208182) and NFATc1 (Cell Signaling Technology, #4389; BioLegend, #649601). Assay conditions. Briefly, ChIP-seq assays are performed in primary human and murine CD8+ T cells, utilizing 10 million cells / per assay. Primary CD8+ T cells are polyclonally activated in vitro by Atty. Dkt. No.: 116639-2710 using anti-CD3 and ant-CD28 antibodies, and treated with TGF- β (20ng / ml) for 6 hours and 24 hours. To optimize the ChIP assay conditions for SMAD1 / 2 / 3 and NFAT1c, Applicant varies fixation conditions and post-immunoprecipitation washing steps to improve the signal-to-noise ratio, which is assessed by ChIP-PCR for enrichment in binding sites known to be occupied by these TFs. With good ChIP-grade antibodies. Applicant’s ChIP-sequencing process, known as ChIPmentation121,122, efficiently prepares libraries from ChIP DNA for sequencing, even from low DNA amounts. Applicant sequences these libraries using the Illumina NovaSeq 6000 platform, generating >40 million 100bp paired-end reads per assay. Analysis. Applicant has extensive experience in analyzing ChIP-seq datasets123- 125. Applicant will follow ENCODE guidelines126 for mapping and peak calling and include independent biological replicates for all ChIP-seq assays to assess the reproducibility. As controls, Applicant includes T cells not treated with TGF-β. These studies confirm if NFAT1c and SMAD proteins bind to C1,C2, or C3 enhancers and / or the promoter of GPR25. (ii) CRISPRi studies. The binding of SMAD proteins or NFAT to cis-regulatory regions (C1,C2,C3) in the GPR25 locus does not imply that SMAD is regulating GPR25 expression. It is important to show that these SMAD-bound regions are indeed functioning as enhancers for GPR25. To demonstrate this, Applicant utilizes CRISPRi (dCas9-KRAB) assays, as described122, to silence the cis-regulatory elements (C1, C2 or C3) that bind SMAD or NFAT in activated CD8+ T cells treated with TGF- β and then determines the effects on GPR25 gene expression by qPCR. As controls, Applicant utilizes non-targeting sgRNAs. Applicant has optimized this assay to work in primary human T cells, and have tested ~10 cis-regulatory elements in a few months, as described in Chandra et al Nature Genetics 2021122.. To ascertain whether SMAD binding is indispensable for the activity of these enhancers, Applicant will utilize only the catalytically dead Cas9 protein (dCas9) along with tiling guide RNAs to target multiple regions) in and around the predicted SMAD binding sites in C1, C2 or C3 enhancer. Because dCas9 lacks any silencing domain, binds to targeted chromatin with high affinity and effectively prevents the binding of SMAD proteins. Thus enabling us to examine if SMAD binding is required for the activity of GPR25 enhancers. Applicant has extensively used this assay to narrow down functional SNPs in enhancers (Nature Genetics Atty. Dkt. No.: 116639-2710 2021122). Together, these CRISPR-based assays define the mechanism by which TGF-β positively regulates the expression of GPR25. The role of NFAT, the transcription factor downstream of TCR signaling, will also be assessed. Results. Applicant determines if SMAD and NFAT proteins bind to the GPR25 locus, implying their potential to directly regulate GPR25 expression. The results demonstrate that the regions bound by SMAD display enhancer activity that is dependent on SMAD binding, thus confirming that GPR25 is a bona-fide target gene of TGF- β. While Applicant’s initial focus is on determining whether GPR25 is the direct target genes of SMAD and NFAT, Applicant is aware that other transcription factors and signaling pathway may also play a role. Because IL-15 signaling is important for TRM cell development127-129, Applicant determines if IL-15 induces GPR25 expression. Applicant examines binding of STAT5, down-stream of IL-15 signaling130, to enhancers in the GPR25 locus. (ii) CRISPR-based assays may have lower silencing efficiency at certain genomic regions. Applicant has extensive experience with these assays. Applicant also consider guide RNAs targeting nearby regions to improve its efficiency. (iii) Broad silencing with CRISPRi assays. To precisely test if SMAD binding is required for the C1-C3 enhancers to regulate GPR25 expression, Applicant considers CRISPR-mediated homology-directed recombination (HDR) in primary CD8+ T cells to generate isogenic cells with targeted deletion of ~20-30bp SMAD binding site in the GPR25 enhancers. Applicant has performed CRISPR-mediated HDR to test the function of a single nucleotide polymorphism (SNP)122. Example 5 GPR25 Mediates its effect on TRM cells Applicant’s studies have shown that Gpr25 plays a plays a key role in supporting the development and maintenance of TRM cells in the liver and lungs. However, the signaling pathways and mechanisms through which Gpr25 mediates its effects are not known. Applicant demonstrates Gpr25 modulates TGF- β signaling to influence the development of TRM cells. GPR25 inhibits cAMP signaling. GPR25 is coupled to the Gαi transducer protein that inhibits adenylate cyclase activity and thus reduces cAMP signaling34. Because GPR25 is an orphan GPCR with no known endogenous ligand, effects of ligand-dependent signaling Atty. Dkt. No.: 116639-2710 cannot be tested. However, a recent report found that GPR25 exhibited significant ligand- independent i.e., constitutive inhibition of cAMP signaling under both baseline and stimulated conditions (using forskolin, an exogenous agent that activates adenylate cyclase and cAMP signaling)72. Another report showed that non-mammalian vertebrate GPR25 can inhibit cAMP signaling in a ligand-dependent manner131. Based on these data, Applicant reasons that GPR25 signaling is likely inhibits cAMP pathway and its downstream targets in T cells. cAMP pathway inhibits TGF- β signaling. Studies in other cellular systems have shown then cAMP signaling can inhibit the expression of TGF- β target genes by modulating SMAD signaling132-135. Notably, heightened cAMP signaling activates cAMP-response element binding protein (CREB), which in turn recruits the transcriptional co-activator p300 away from SMADs, thereby restricting the transcriptional activity of SMAD i.e., TGF- β signaling133. TGF- β signaling regulates TRM cell development. The two cytokines, TGF β and IL-15, play central roles in shaping the TRM gene expression programs. TGF β directlyregulates expression of the following key genes55,67,127-130,136-139: (i) CD103, encodes for⍺E integrin, that is expressed by TRM cells at barrier sites; (ii) KLF2, encodes a transcriptionfactor that regulates expression of S1PR1, a sphingosine-1-phosphate receptor that promotes egress of cells from tissues140; (iii) ZEB2, a transcription factor that regulates expression of S1PR5, and (iv) IL-15 receptor (IL-15RA) expression that supports responses to IL-15. Without being bound by theory, these data support a hypothesis that GPR25, through the inhibition of the cAMP pathway, enhances (releases inhibition of) TGF β signaling, thereby supporting the development of TRM cells. To lend support for this hypothesis, Applicant performed single-cell transcriptome analysis of Gpr25+ / + and Gpr25- / - OT-I memory T cells that were isolated from lung tissue 30 days after LCMV-OVA infection (i.t.) (FIG. 5F). Gene set enrichment analysis showed significant positive enrichment of TGF- β signaling genes in Gpr25+ / + memory T cells when compared to versus Gpr25- / - T cells (not shown). Based on transcriptomic features, OT-I T cells clustered into two major subsets; notably, a greater fraction of Gpr25+ / + versus Gpr25- / - OT-I memory T cells (62% versus 38%) were observed in cluster 0 (FIG. 5F, left). Compared to Atty. Dkt. No.: 116639-2710 cluster 1, cluster 0 cells that were enriched for Gpr25+ / + T cells expressed lower levels of transcripts encoding for molecules linked to effector properties like perforin, granzyme B, granzyme A, and higher levels of transcripts encoding for molecules linked to stem-like memory properties such as Tcf1 and IL7R (FIG. 5F and 5E), which suggested that Gpr25 is likely to promote the formation of long-lived memory cells with stem-like properties as opposed to the differentiation into short-lived effectors. Most notably, T cells in cluster 0 compared to cluster 1 displayed lower expression of transcripts encoding for the transcription factors ZEB2 and S1PR5, a sphingone-1-phosphate receptor that promotes egress of cells from tissues140 (FIG. 5E, 5F). A recent study showed that the robust generation of TRM cells requires down- regulation of transcription factor ZEB2 and its target gene S1PR5 by TGF- β signaling in the tissues55, which in turn promotes sequestration of cells in the tissues. Taken together, it is tempting to speculate that Gpr25 may play a role in the downregulation of ZEB2-S1PR5 axis, potentially by modulating TGF- β signaling and thus favoring the generation of TRM cells in the lungs. Strategy and Methods. To determine if Gpr25 enhances TGF- β signaling in T cells, Applicant performs gain-of-function (forced expression of Gpr25), loss-of-function (Gpr25- / - T cells i.e., genetic knockout) and rescue studies. (i) In vitro studies. While TRM cells express Gpr25, their relatively low abundance in vivo makes it challenging to isolate a sufficient number of cells required for extensive in vitro studies. Instead, Applicant uses naïve CD8+ T cells for these assays. Because Gpr25 is not expressed by naïve CD8+ T cells, Applicant forces expression of Gpr25 using viral transduction methods. Briefly, mouse Gpr25 cDNA construct was cloned into pMSCV-Thy1.1 retroviral vector. Empty vector or Gpr25 plasmid was transfected into Plat-E cells to generate retroviral supernatants, which was used for transducing activated T cells. Transduced T cells were expanded for 2-3 days in IL-2, and Thy1.1-expressing cells were sorted for further functional studies. Applicant achieved 30% transduction efficiency in primary CD8+ T cells (not shown). Assays and Readouts. Here, Applicant treats CD8+ T cells with forced expression of Gpr25 and control T cells (empty vector transduced cells) with TGF- β (20 ng / ml) and compares their responses at different time points (4, 24 and 48 hours) using multiple assays / readouts that include: (a) Flowcytometry and qPCR to assess expression of key TGF-β target genes such as Atty. Dkt. No.: 116639-2710 CD103, Klf2, S1pr1, S1pr5, and Zeb2. In addition, Applicant assess if forced expression of Gpr25 in T cells leads to increased expression of TGF- β receptor II (TGF-β R2)141, potentially augmenting TGF- β sensing. (b) Bulk RNA-seq analysis to identify genes that are differentially expressed following forced expression of Gpr25. Perform GSEA to determine if global TGF-β signature genes are enriched in T cells with forced expression of Gpr25. (c) SMAD-ChIP-seq to definitively determine if forced Gpr25 expression in T cells results in enhanced binding of SMAD proteins at the TGF- β target genes (Aim 2A). (ii) In vivo studies. Applicant determines if forced expression of Gpr25 in CD8+ T cells promotes the development of TRM cells by enhancing TGF- β signaling. Applicant transfers congenically distinct OT-1 T cells with forced Gpr25 expression (generated as above), as well as control groups with an empty vector expressing cells and Gpr25- / - OT-I T cells, into separate cohorts of mice prior to LCMV infection (as shown in FIG. 5). Applicant evaluates the phenotype and transcriptional features of congenically-marked transferred cells in the lungs at day 14 and day 30 following infection. Readouts. (a) Phenotype. Applicant examines expression of marker genes linked to TRM cells (CD69, CD103, CXCR6) and TCM cells (CD62L, CD127); (b) Single-cell RNA-seq, as described in FIG. 5F, at early (day 14) and late (day 30) timepoints to determine if forced Gpr25 expression skews the development of memory T cells towards TRM phenotype by restraining the expression of TGF- β target genes that promote tissue egress (Klf2-S1pr1 and Zeb2-S1pr5 axis). Applicant examines if signature genes in TGF- β pathway are enriched in T cells with forced Gpr25 expression. (c) Single-cell ATAC-seq analysis to determine if forced Gpr25 expression increases chromatin accessibility at key TGF- β signature genes. These results can confirm the hypothesis that Gpr25 mediates its effects by augmenting the TGF- β signaling pathway. (iii) Rescue studies. Gpr25-deficient T cells display defects in TRM cell development (FIG. 3-5). If Gpr25 mediates its effects primarily by impairing TGF- β signaling then restoring TGF- β signaling should rescue the phenotype, i.e., development of TRM cells. Here, Applicant forces expression of the constitutively active TGF- β receptor (TGF-β RICA)67,142 in Gpr25-deficient and Gpr25-sufficient (controls) OT-1 T cells and assess its impact on lung TRM cell development in the LCMV-infection model, as described (FIG. 5). Atty. Dkt. No.: 116639-2710 Constitutively active TGF- β signaling restores the capacity of Gpr25-deficient T cells to develop into lung TRM cells by restricting their capacity to egress from the lungs. Forced expression of Gpr25 results in enhancement of TGF- β signaling in T cells, which is evident through changes in the expression levels, SMAD binding and chromatin accessibility of TGF- β target genes. Although enhanced TGF- β signaling is Applicant’s primary hypothesis, Applicant’s alternate hypothesis is ‘IL-15 signaling pathway is modulated by Gpr25 to promote TRM development’. The cAMP signaling pathway, which is inhibited by Gpr25, has been shown to inhibit IL-2 and its downstream signaling pathway (JAK3 / STAT5)143. Considering that IL-15 utilizes similar receptors and engages downstream STAT3 / 5 pathway144, it is highly plausible that cAMP may also inhibit IL-15 signaling. Notably, IL-15 signaling has been shown to support the expansion and survival of developing TRM cells127-129, while also inducing the expression of Hobit53, a critical TRM transcription factor that down-regulates expression of genes involved in tissue egress / TCM such as S1PR1 and CCR753. Several studies have shown that IL15 receptor-deficient T cells display profound defects in the development and maintenance of TRM cells in vivo127-129. Based on this rationale, here, Applicant will test if IL-15 signaling pathway is also modulated by Gpr25 (alternative hypothesis). Because of Applicant’s unbiased approaches (RNA-seq, ATAC-seq), Applicant determines if forced expression of Gpr25 impacts target genes and enhancers that are downstream of IL-15 signaling pathway. In the in vitro models, Applicant treats T cells with forced expression of Gpr25 and controls T cells (empty vector transduced cells) with IL-15 and assesses its effects (as for TGF- β), including phosphorylation of STAT5, the key downstream signaling mediator of IL-15. Utilizing Applicant’s unbiased datasets, Applicant is able to determine if Gpr25 modulates the activities of other transcriptional regulators involved in the development of TRM cells such as Blimp-1, Runx3 and Id3. (ii) Lack of endogenous ligand for Gpr25. Given that ligand-independent constitutive activity has been reported for Gpr2572, Applicant observe effects in vitro even in the absence of endogenous ligand. (iii) Organ-specific effects. Due to the critical role of lung TRM cells in infection control and mucosal immunity, Applicant’s focuses on examining the downstream effects of Gpr25 in lung TRM cells. However, Applicant’s studies have shown that Gpr25 is also important for the development of liver TRM cells. Recent studies have shown that Atty. Dkt. No.: 116639-2710 TRM cells in various tissues, such as the liver and skin, utilize distinct yet overlapping signaling pathways67. Therefore, Gpr25 may modulate different pathways in liver TRM cells. Example 6: TGF-β Regulates Expression of GRP25 Applicant performs ChIP-seq studies to determine if SMAD proteins, downstream of TGF-β signaling, bind to cis-regulatory elements in the GPR25 locus. Subsequently, Applicant utilizes CRISPR-based assays to assess if SMAD-bound regions enhance the expression of GPR25 in T cells. (B) Applicant’s preliminary studies (FIG. 5) support the hypothesis that Gpr25 may modulate TGF- β signaling to influence the development of TRM cells. Applicant performs gain-of-function (forced expression of Gpr25), loss-of-function (Gpr25- / - T cells i.e., genetic knockout) and rescue studies (forced expression of constitutively active TGF- β RICA) both in vitro and in vivo, using mouse models of viral infection. Table 1 24 h 48 h 8 1 9 7 2 3 4 8 4 2 Atty. Dkt. No.: 116639-2710 Table 2 No TGFβ IL-15 24h 48h 24h 48h 24h 48h 3 2 5 7 4 4 8 Table 3 Spleen Liver siIEL 8 2 7 4 6 8 Atty. Dkt. No.: 116639-2710 REFERENCES: 1. Schenkel, J. M. & Masopust, D. Tissue-resident memory T cells. Immunity 41, 886-897, doi:10.1016 / j.immuni.2014.12.007 (2014). 2. Kok, L., Masopust, D. & Schumacher, T. N. 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Claims

Atty. Dkt. No.: 116639-2710 WHAT IS CLAIMED IS:

1. A method of one or more of: modulating an immune response to a tumor or cancer cell or an infection in a patient, treating cancer or a tumor in a cancer patient, or eliciting an anti-cancer or tumor response in a patient, treating or ameliorating an infection in a patient, comprising modulating expression or activity of G Protein-Coupled Receptor 25 (GPR25) in a T cell in the patient.

2. The method of claim 1, wherein the expression or activity of GPR25 is modulated by administering to the patient an effective amount of an agent that targets GPR25 in the T cell.

3. The method of claim 2, wherein the agent comprises a small molecule or a protein selected from the group of: Transforming Growth Factor-β (TGF-β), Nuclear Factor of Activated T-cells (NFAT), or Suppressor of Mothers Against Decapentaplegic family member 1 (SMAD1), or equivalents thereof.

4. The method of claim 3, wherein the agent comprises TGF-β.

5. The method of any one of claims 1 to 4, wherein the T cell is selected from the group of: an activated T cell; a tissue-resident memory (TRM) cell; and a stem T cell.

6. The method of claim 5, wherein the activated T cell is specific for a tumor-specific antigen or a tumor-associated antigen expressed by the cancer or tumor cell, wherein the tumor- associated antigen is optionally overexpressed by the tumor cell.Atty. Dkt. No.: 116639-2710 7. The method of claim 6, wherein the modulation comprises activating the T cell by agonizing the expression or activity of GPR25 in the T cell.

8. The method of any one of claims 2 to 7, wherein the agent is bispecific and binds to GPR25 and binds to a second receptor expressed by the T cell.

9. The method of claim 8, wherein the second receptor is selected from a group of: CXCR5, CXCR6, CD8, CD103, CD49A, CD69, CD3, CD28, CD8 or PD1.

10. The method of claim 8, wherein the receptor is CXCR5.

11. The method of any one of claims 2 to 7, wherein the agent that binds to GPR25 comprises an agonistic antibody.

12. The method of any one of claims 8 to 11, wherein the agent is a bispecific antibody that binds to GPR25 and a second molecule expressed by the T cell.

13. The method of any one of claims 2 to 7, wherein the agent binds to GPR25 and binds to a tumor antigen expressed by the tumor cell that is optionally overexpressed by the tumor cell.

14. The method of claim 13, wherein the tumor antigen is a tumor-associated antigen or a tumor-specific antigen.

15. The method of claim 14, wherein the tumor-associated antigen is overexpressed by the tumor cell.

16. The method of any one of claims 13 to 15, wherein the tumor antigen is a lung cancer antigen or a lymphatic tissue antigen.

17. The method of claim 13, wherein the tumor antigen is selected from the group of: MAGE-D4B, PSMA, HER2, HER3, EGFR, AFP, CEA, CA-125, MUC-1, ETA, MUC-1, BAGE, GAGE-1, MAGE-A1, NY-ESO-1, Gp100, Melan-A / MART-1, Prostate-specific antigen, Mammoglobin-A, Alpha-fetoprotein, HER-2 / neu, P53, K-ras, or TRP-2 / INT2.Atty. Dkt. No.: 116639-2710 18. The method of any of claims 1 to 17, wherein the cancer or tumor cell and / or the cancer or tumor is selected from a cancer or tumor of a tissue or cell from the group of: circulatory system; respiratory tract; gastrointestinal system genitourinary tract; live; bone; nervous system; reproductive system; hematologic system; oral cavity; skin and other tissues comprising connective and soft tissue, retroperitoneum and peritoneum, eye, intraocular melanoma, and adnexa, breast, head or / and neck, anal region, thyroid, parathyroid, adrenal gland and other endocrine glands and related structures, and lymph nodes, optionally wherein the cancer is a solid tumor or alternatively wherein the cancer is a liquid cancer, and further optionally wherein the cancer is a primary cancer or a metastasis and / or a cancer selected from a carcinoma, a sarcoma, a myeloma, a leukemia, or lymphoma, testis cancer, brain cancer, a metastasis or recurring cancer a non-small cell lung cancer (NSCLC) and / or head and neck squamous cell cancer (HNSCC).

19. The method of claim 18, wherein the cancer or tumor cell and / or the cancer or tumor is selected from a cancer or tumor of a tissue or cell from the respiratory tract or lymph nodes.

20. The method of claim 18, wherein the cancer or tumor cell and / or the cancer or tumor is selected from a cancer or tumor of a tissue or cell from the respiratory tract 21. The method of any one of claims 1 to 20, wherein the cancer is localized or metastatic cancer.

22. The method of claim 21, wherein the cancer is metastatic lung cancer.

23. The method of any one of claims 1 to 22, wherein the patient is a human patient.

24. The method of any one of claims 1 to 23, wherein the patient has reduced expression of GPR25 compared to that of a healthy, non-diseased subject.

25. The method of any one of claims 1 to 24, further comprising resecting the tumor or cancer prior to modulating the expression or activity of GPR25 in the T cell in the patient.Atty. Dkt. No.: 116639-2710 26. The method of any one of claims 1 to 25, wherein the modulating expression or activity of GPR25 in a T cell is administered as a first-line, a second-line, a third-line, a fourth-line or fifth-line therapy.

27. The method of any one of claims 1 to 26, further comprising administering an effective amount of a different anti-cancer agent to the patient.

28. The method of any one of claims 1 to 27, wherein the treating cancer or a tumor in a cancer patient comprises one or more of a reduction in tumor burden, longer overall survival or prolonged time to tumor progression.

29. A method for screening for a GPR25 anticancer therapy comprising contacting a first sample of T cells with an amount of a test agent that binds to GPR25 and a second agent that binds a tumor antigen, and assaying for increased expression of GPR25 in the T cell.

30. The method of claim 29, wherein increased expression of GPR25 in the T cell is an indication that the agent is a GPR25 anticancer therapy.

31. A method of modulating GPR25 in a subject, comprising administering a bispecific antibody that targets and binds to GPR25 and a second receptor expressed by a T cell.

32. The method of claim 31, wherein the receptor is selected from CXCR5, CXCR6, CD8, CD103, CD49A, CD69, CD3, or PD1.

33. The method of claim 31 or 32, wherein the T cell is a stem T cell.

34. The method of any one of claims 31 to 33, wherein the subject is a human patient.

35. A method of determining prognosis of a subject having cancer comprising contacting T cells isolated from the subject with an antibody or agent that recognizes and binds to GPR25 to determine the frequency of T cells expressing GPR25 in tumor cells, wherein a high density of GPR25 in T cells indicates a more positive prognosis or wherein a low density of GPR25 in T cells indicates a more negative prognosis, optionally wherein the more negative prognosisAtty. Dkt. No.: 116639-2710 comprises a decreased probability in survival, and wherein the more positive prognosis comprises an increased probability in survival.

36. A method of determining the responsiveness of a subject to cancer therapy that modulates GPR25 comprising contacting T cells isolated from the subject with an antibody or agent that recognizes and binds to GPR25 to determine the frequency of GPR25 expressing T cells in the subject, wherein a high frequency of GPR25 T cells indicates an increased likelihood of responsiveness to a cancer therapy.

37. The method claim 36, wherein the cancer therapy comprises an agent that modulates the expression and / or activity of GPR25 in the subject.

38. The method of claim 35, wherein the density of GPR25 in T cells in the subject is compared to a healthy, non-diseased subject.

39. The method of any one of claims 35 to 38, further comprising administering a cancer therapy that modulates GPR25 to the subject.

40. The method of claim 39, wherein the cancer therapy is an agent that binds to GPR25.

41. The method of claim 40, wherein the agent is an agonistic antibody targeting GPR25.

42. The method of any one of claims 35 to 41, wherein the T cell is contacted with an agent, optionally including a detectable label or tag.

43. The method of claim 42, wherein the detectable label or tag comprises a radioisotope, a metal, horseradish peroxidase, alkaline phosphatase, avidin or biotin.

44. The method of claim 42 or 43, wherein the agent comprises a polypeptide that binds to an expression product encoded by GPR25, or a polynucleotide that hybridizes to a nucleic acid sequence encoding all or a portion of GPR25.Atty. Dkt. No.: 116639-2710 45. The method of claim 44, wherein the polypeptide comprises an antibody, an antigen- binding fragment thereof, or a receptor that binds to the GPR25.

46. The method of claim 45, wherein the antibody is an IgG, IgA, IgM, IgE or IgD, or a subclass thereof.

47. The method of claim 46, wherein the IgG is an IgG1, IgG2, IgG3 or IgG4.

48. The method of any one of claims 45 to 47 wherein the antigen binding fragment is a Fab, Fab’, F(ab’)2, Fv, Fd, single-chain Fvs (scFv), disulfide-linked Fvs (sdFv) or VL or VH.

49. The method of any one of claims 44 to 48, wherein the agent is contacted with the sample in conditions favoring binding of the agent to GPR25.

50. The method of any one of claims 23 to 49, wherein the method comprises detection by immunohistochemistry (IHC), in-situ hybridization (ISH), ELISA, immunoprecipitation, immunofluorescence, chemiluminescence, radioactivity, X-ray, nucleic acid hybridization, protein-protein interaction, immunoprecipitation, flow cytometry, Western blotting, polymerase chain reaction, DNA transcription, Northern blotting and / or Southern blotting.

51. The method of any one of claims 29, wherein the sample comprises cells, tissue, an organ biopsy, an epithelial tissue, a lung, respiratory or airway tissue or organ, a circulatory tissue or organ, a skin tissue, bone tissue, muscle tissue, head, neck, brain, skin, bone and / or blood sample.

52. A method of treating cancer in a subject, comprising administering a T cell having increased expression of GPR25 to the subject.

53. The method of claim 52, wherein the cancer or tumor cell and / or the cancer or tumor is selected from a cancer or tumor of a tissue or cell from the respiratory tract or lymph nodes.

54. The method of claim 52, wherein the cancer or tumor cell and / or the cancer or tumor is selected from a cancer or tumor of a tissue or cell from the respiratory tract.Atty. Dkt. No.: 116639-2710 55. The method of any one of claims 52 to 54, wherein the cancer is metastatic cancer.

56. The method of claim 55, wherein the cancer is metastatic lung cancer.

57. The method of any one of claims 52 to 56, wherein the subject is a human subject.

58. The method of any one of claims 52 to 57, wherein the patient has reduced expression of GPR25 compared to that of a healthy, non-diseased subject.

59. The method of any one of claims 52 to 58, wherein the T cell is selected from the group of: an activated T cell; a tissue-resident memory (TRM) cell; a stem T cell.

60. The method of claim 59, wherein the activated T cell is specific for a tumor-specific antigen or a tumor-associated antigen expressed by the tumor cell, wherein the tumor-associated antigen is optionally overexpressed by the tumor cell.

61. The method of claim 59, wherein the T cell is a TRM cell.

62. A method of promoting the development of TRM cells in a subject, comprising administering an agent that modulates expression of GPR25 to the subject.

63. The method of claim 62, wherein the TRM cells are in the lung tissue or liver tissue of the subject.

64. The method of claim 62, wherein the agent is administered to the lung tissue or liver tissue of the subject.

65. A method of promoting development of stem-like TRM cells in a subject, comprising administering an agent that modulates expression of GPR25 to the subject.

66. The method of any one of claims 62 to 65, wherein the agent comprises a small molecule or a protein selected from the group of: Transforming Growth Factor-β (TGF-β), Nuclear Factor of Activated T-cells (NFAT), or Suppressor of Mothers Against Decapentaplegic family member 1 (SMAD1), or equivalents thereof.

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