ARGINASE POLYPEPTIDES1

Abstract

The present invention relates to novel polypeptides derived from arginase 1. The invention also relates to polynucleotides encoding the polypeptides. The invention further relates to compositions comprising the polypeptides and polynucleotides. The invention further relates to uses of the polypeptides, polynucleotides, and compositions.

Description

ARGINASE POLYPEPTIDES1 Field of invention The present invention relates to novel polypeptides derived from arginase 1. The invention also relates to polynucleotides encoding the polypeptides. The invention further relates to compositions comprising the polypeptides and polynucleotides. The invention further relates to uses of the polypeptides, polynucleotides, and compositions. Background of the invention Arginase is an enzyme that catalyzes a reaction converting the amino acid L-arginine into L-ornithine and urea. This depletes the arginine microenvironment and leads to suppression of tumor-specific cytotoxic T lymphocyte responses. Increased arginase activity has been detected in cancer cells from patients with breast, lung, colon, or prostate cancer. Both in vitro and in vivo, mouse macrophages transfected with a rat arginase gene have been shown to promote the proliferation of co-cultured tumor cells. Furthermore, induction of arginase expression by macrophages has been shown to increase tumor vascularization through polyamine synthesis. Results from a murine lung carcinoma model showed a subpopulation of tumor-associated mature myeloid cells expressing high levels of arginase.These tumor-associated myeloid cells depleted extracellular L-arginine, which inhibited the antigen-specific proliferation of tumor-infiltrating lymphocytes (TILs). Injection of an arginase inhibitor blocked lung carcinoma growth in mice. This shows how inducing arginase expression in tumor cells and tumor-associated myeloid cells could promote tumor growth by suppressing antitumor immune responses through negative effects on TILs. Myeloid-derived suppressor cells (MDSCs) inhibit the activation, proliferation, and cytotoxicity of effector T cells and natural killer cells, and induce the differentiation and expansion of regulatory T cells (Tregs). Both cancer cells and MDSCs can suppress T cells by manipulating L-arginine metabolism through the enzymes nitric oxide synthase (NOS) and arginase. Many tumors exhibit expression of these enzymes. Increased levels of arginase and inducible NOS (NOS) in tumor microenvironments lead to arginine depletion. Several studies emphasize the importance of this altered tumor arginine metabolism in suppressing tumor-specific T-cell responses, and acute myeloid leukemia (AML) blast cells have recently been shown to exhibit the ability to inhibit arginase-dependent T-cell and hematopoietic stem cell proliferation. Similarly, arginase and NOS inhibitors reduce the suppressive activity of AML. Summary of the invention The present inventors have previously identified a 50-amino-acid region of arginase 1 that is a hotspot for immunogenicity. This region corresponds to positions 161-210 of full-length human arginase 1 (SEO ID NO: 10). The region and peptides derived therefrom are described in WO2018065563. (Note that the terms arginase 1, Arg1, and arginasal are used interchangeably herein.) The present inventors have now identified that a specific subset of polypeptides derived from this region is particularly effective in stimulating immune responses. Therefore, the polypeptides of the present invention are expected to be particularly effective in stimulating a beneficial immune response against arginase 1 and against cells expressing arginase 1. The development of novel immune therapies for cancer requires a thorough understanding of the molecules involved in pathogenesis, as well as the specific proteins recognized by the immune system.In the clinical setting, the induction of specific arginase immune responses could, in addition to destroying cancer cells, support overall anticancer immune responses by suppressing the immunosuppressive function of arginase-expressing cells, particularly MDSCs and tumor-associated macrophages (TAMs). Consequently, because arginase-expressing cells antagonize the desired effects of other immunotherapeutic approaches targeting myeloid dendritic cells, such as vaccination with the polypeptides of the present invention, it would be highly synergistic with additional anticancer immunotherapy. The present invention provides: An isolated polypeptide consisting of any one of the following Lbfrrnn / Lznz / e / YiAi amino acid sequences: to. ISAKDIVYIGLRDVDPGEHYILKTLGIKYFSMTEVDRL (SEQ ID NO:1); b. ISAKDIVYIGLRDVDPGEHYIIKTLGIKYFSMTEVDKL (SEQ ID NO: 2); c. ISAKDIVYIGLRDVDPGEHYILKTLGIKYFSM (SEQ ID NO:3); d. ISAKDIVYIGLRDVDPGEHYIIKTLGIKYFSM (SEQ ID NO:4); and. ISAKDIVYIGLRDVDPGEHYILKTLGIKYFSMTEVDRLGIGK (SEQ ID NO:5); F. ISAKDIVYIGLRDVDPGEHYIIKTLGIKYFSMTEVDKLGIGK (SEQ ID NO:6). The present invention further provides a polynucleotide encoding a polypeptide of the invention, optionally comprised within a vector. The present invention also provides a composition comprising a polypeptide or polynucleotide of the invention, at least one pharmaceutically acceptable diluent, carrier or preservative, and optionally, an adjuvant. This disclosure also provides a method for treating or preventing a disease or condition in a subject, the method comprising administering to the subject a polypeptide, polynucleotide, or composition of the invention. Brief description of the figures Figure 1 shows responses against long Arg1-derived peptides ELISPOT responses of IFNγ against the peptides ArgLong, ArgLong2, and ArgLong3 in PBMCs from four healthy donors (HD). Bars represent the mean number of points per well ± standard error of the mean. Images of the corresponding ELISPOT wells with and without peptide addition are also shown for each donor. Experiments were performed with 5 x 10⁵ PBMCs / well in triplicate. TNTC: too numerous to count. * - p < 0.05 according to the non-distributed resampling rule (DFR). Figure 2 shows the responses against ArgLong2 compared to 20-mer peptides ELISPOT responses of IFNγ against Argi7i-i9o, Argi8i-200, Arg191, and ArgLong2 in 19 healthy donors (top) and 16 cancer patients (bottom). Each dot represents the mean number of peptide-specific dots for a single patient / donor. Responses were calculated by subtracting the mean dot count in control wells from the mean dot count in peptide-stimulated wells. Experiments were performed with 4.5–5 x 10⁵ PBMCs / well for healthy donors and 2.2–5 x 10⁵ PBMCs / well for cancer patients, in triplicate or duplicate. Responses against ArgLong2 Lirfrrnn / Lznz / e / YiAi were too numerous to count (TNTC) in six healthy donors and two cancer patients and settled at > 500 points. Figure 3 shows that CD4+ and CD8+ T lymphocytes respond to ArgLong2 in vitro and ex vivo 3A - In vitro responses against ArgLong2 in CD4+ (left) and CD8+ (right) T lymphocytes in intracellular PBMC staining from two healthy donors and one breast cancer patient. PBMCs were stimulated with ArgLong2 and a low dose of IL-2 for one week prior to the ELISPOT assay. 3B - Ex vivo responses against ArgLong2 in CD4+ (left) and CD8+ (right) T lymphocytes in PBMC intracellular staining from two cancer patients, without prior stimulation (BC-breast cancer, MM-malignant melanoma). Figure 4 shows that ArgLong2-specific CD4+ and CD8+ cells are memory T lymphocytes 4A - Ex vivo responses against ArgLong2 in four healthy donors (HD) and two cancer patients (BC-breast cancer, MM-malignant melanoma). Experiment performed in triplicate with 1-5x105 cells / well. 4B - ELISPOT of ex vivo IFNy-classified CD4+ (CD45RO+) memory T lymphocytes from PBMCs of four healthy donors and two cancer patients (breast cancer and malignant melanoma). Experiment performed in triplicate with 1-3x105 cells / well. 4C - ELISPOT of IFNy ex vivo of PBMC-sorted CD8+ memory T lymphocytes (CD45RO+) from two healthy donors. Experiment performed in duplicate or singlet with 1x105 cells / well. The bars represent the average point counts in the control and peptide + EEM stimulated wells. Figure 5 shows that IL-4 stimulation activates ArgLong2-specific T lymphocytes A - IFNγ ELISPOT for ArgLong2 responses in PBMCs from melanoma patients stimulated with IL-4 and / or IL-2 for one week. Unstimulated PBMCs were used as a control. Overlapping bars show the midpoint counts of the control and peptide-+EM stimulated wells. Experiment performed in triplicate with 3 x 10⁵ cells / well. B - Specific ArgLong2 responses in PBMCs from six healthy donors (HD) and two cancer patients (BC - breast cancer, MM - malignant melanoma) after IL-2 stimulation Lbfrrnn / Lznz / e / YiAi (120U / ml) or IL-4 (100U / ml) were administered for one week. Cells without cytokine stimulation were used as a control. Responses were calculated as the difference in midpoint counts between peptide-stimulated and control wells in ELISPOT. The experiment was performed in triplicate or duplicate with 3 x 10⁵ cells / well. Figure 6 shows the ArgLong2-specific IFNy immune responses mounted in vivo after immunization Four mice were vaccinated with the ArgLong2 peptide, and the immune response against the peptide was assessed after 7 days using IFN-γ ELISPOT. Cells from the spleen and draining lymph nodes of individual mice were subjected to the ELISPOT assay. Bars represent the mean number of points. ELISPOT was performed in triplicate with and without the addition of the ArgLong2 peptide. TNTC indicates too numerous to count. ** indicates p < 0.01 according to the non-distribution resampling (DPR) method. Figure 7 shows that vaccination with ArgLong2 induces antitumor effects in the MC38 colon adenocarcinoma tumor model 0.5 x 10⁶ MC38 tumor cells were inoculated subcutaneously into the right flank of 30 mice on day 0. Vaccinations were initiated on the same day. The 15 mice in the treatment group were treated with 100 pg of ArgLong2 in emulsion with Montanide, and the 15 mice in the control group were treated with H₂O in emulsion with Montanide. p = 0.030 according to the mixed-effects analysis. Figure 8 shows that vaccination with ArgLong2 induces antitumor effects in the B16F10 melanoma tumor model On day 0, 0.5 x 10⁶ B16F10 tumor cells were injected subcutaneously into the right flank of 30 mice. Vaccinations began on the same day. The 15 mice in the treatment group were treated with 100 pg of ArgLong2 in emulsion with Montanide, and the 15 mice in the control group were treated with H₂O in emulsion with Montanide. Treatment was stopped after three vaccinations. Mice were sacrificed when tumor volume exceeded 864 mm³. Figure 9 shows that ArgLong2-specific T lymphocyte clones recognize arginase-1-expressing THP-1 cells A and B - The ArgLong2-specific CD4 T cell clone recognizes THP1 cells when arginase 1 expression is induced by the Th2 cytokine, quantified by intracellular cytokine staining. C - qPCR data showing that stimulation Lbfrrnn / Lznz / e / YiAi prior with IL-13 of THP-1 cells induces arginase 1 expression. Figure 10 shows that in vitro cytokine stimulation alone is sufficient to expand T-cell responses to the ArgLong2 epitope PBMCs were treated with either the Th2 arginase-adducting cytokine 1 (IL-4 / IL-13) or the peptide ArgLong2 for 7 days before ArgLong2-specific T lymphocytes were quantified in vitro by IL-Nγ ELISPOT. Brief description of the sequences SEQ ID NO: 1 - 9 are each an amino acid sequence of a polypeptide derived from the region corresponding to positions 161-210 of full-length human arginase 1 or murine arginase 1. SEQ ID NO: 10 and 11 are the amino acid sequences of full-length human arginase 1 and murine arginase 1, respectively. SEQ ID NO: 12 is the amino acid sequence of the region corresponding to positions 161-210 of the full-length human arginase 1. SEQ ID NO: 13 is the amino acid sequence of the region corresponding to positions 161-210 of full-length murine arginase 1. Detailed description of the invention It should be understood that different applications of the disclosed products and methods may be adapted to specific technical needs. It should also be understood that the terminology used herein is solely for the purpose of describing particular embodiments of the invention and is not intended to be limiting. Furthermore, as used in this specification and in the appended claims, the singular forms a, one, and the include plural references, unless the content clearly indicates otherwise. Thus, for example, a reference to a polypeptide includes polypeptides and the like. A polypeptide is used herein in its broadest sense to refer to a compound of two or more amino acid subunits, amino acid analogs, or other peptidomimetics. The term polypeptide therefore includes short peptide sequences as well as longer polypeptides and proteins. As used herein, the term amino acid refers to naturally occurring and / or non-natural or synthetic amino acids, including both D and L optical isomers, as well as amino acid analogs and peptidomimetics. Lbfrrnn / Lznz / e / YiAi The terms patient and subject are used interchangeably and usually refer to a human being. All publications, patents, and patent applications cited herein, either above or below, are incorporated herein by reference in their entirety. The present inventors have previously identified a 50-amino-acid region of human and murine arginase 1 that is a hotspot for immunogenicity. This region corresponds to positions 161-210 of full-length human arginase 1 (SEQ ID NO: 10) or full-length murine arginase 1 (SEQ ID NO: 11). The region and peptide fragments derived from it are described in WO2018065563. The present inventors have now identified that a polypeptide consisting of a specific contiguous amino acid sequence from this region is strikingly immunogenic relative to other amino acid sequences in the same region. For the purposes of this document, "immunogenic" means that a polypeptide is capable of eliciting an immune response for arginase 1 protein, preferably when that protein is present in or on cells expressing arginase 1 protein. In other words, the polypeptide can be described as immunogenic for arginase 1. Alternatively, the polypeptide can be described as an immunogenic fragment of arginase 1. The immune reaction is preferably a T-cell response. The immune response can be detected in at least one individual (or in a sample taken from the individual) following administration of the polypeptide to that individual (or to that sample). A polypeptide can be identified as immunogenic using any suitable method, including in vitro methods. For example, a peptide can be identified as immunogenic if it has at least one of the following characteristics: (i) is capable of eliciting IFN-γ producing cells in a PBL population from a healthy subject and / or a cancer patient as determined by an ELISPOT assay, and / or (ii) is capable of in situ detection in a tumor tissue sample of CTLs that are arginase 1 reactive; and / or (iii) is capable of inducing the growth of specific T lymphocytes in vitro. Suitable methods for determining whether a polypeptide is immunogenically active are also described in the examples section below. Lbfrrnn / Lznz / e / YiAi The polypeptide of the invention may consist of: - the amino acid sequence corresponding to positions 169-206 of full-length human arginase 1. This polypeptide may be referred to herein as ArgLong2. Its sequence is provided as SEQ ID NO: 1. - the amino acid sequence corresponding to positions 169-206 of full-length murine arginase 1. This polypeptide may be referred to herein as mArgLong2. Its sequence is provided as SEQ ID NO: 2. - the amino acid sequence corresponding to positions 169-200 of full-length human arginase 1. This polypeptide may be referred to herein as ArgLong3. Its sequence is provided as SEQ ID NO: 3. - the amino acid sequence corresponding to positions 169-200 of full-length murine arginase 1. This polypeptide may be referred to herein as mArgLong3. Its sequence is provided as SEQ ID NO: 4. - the amino acid sequence corresponding to positions 169-210 of full-length human arginase 1. This polypeptide may be referred to herein as ArgLong. Its sequence is provided as SEQ ID NO: 5. - the amino acid sequence corresponding to positions 169-210 of full-length murine arginase 1. This polypeptide may be referred to herein as mArgLong. Its sequence is provided as SEQ ID NO: 6. The polypeptide preferably consists of the amino acid sequence corresponding to positions 169-206 of full-length human or murine arginase 1, i.e., it consists of the amino acid sequence of SEQ ID NO: 1 or 2. That is, the polypeptide is preferably ArgLong2 or mArgLong2. The polypeptide consists, more preferably, of the amino acid sequence corresponding to positions 169-206 of full-length human arginase 1, i.e., it consists of the amino acid sequence of SEQ ID NO: 1. That is, the polypeptide is preferably ArgLong2. In any polypeptide described herein, the amino acid sequence may be modified by one, two, three, four, or five (i.e., up to five) additions, deletions, or substitutions, provided that a polypeptide having the modified sequence exhibits the same or greater immunogenicity for arginase 1 compared to a polypeptide having the unmodified sequence. It is understood that the polypeptide with the modified sequence does not exhibit significantly reduced immunogenicity for arginase 1 compared to the Lbfrrnn / Lznz / e / YiAi polypeptide of the unmodified sequence. Any comparison of immunogenicity between sequences must be performed using the same assay. Unless otherwise specified, modifications to a polypeptide sequence are preferably conservative amino acid substitutions. Conservative amino acid substitutions replace amino acids with other amino acids of similar chemical structure, similar chemical properties, or similar side chain volume. The introduced amino acids may have polarity, hydrophilicity, hydrophobicity, basicity, acidity, neutrality, or charge similar to the amino acids they replace. Alternatively, the conservative substitution may introduce another aromatic or aliphatic amino acid in place of a pre-existing aromatic or aliphatic amino acid.Conservative amino acid shifts are well known in the art and can be selected according to the properties of the 20 main amino acids as defined in Table A1 below. When amino acids have similar polarity, this can also be determined by reference to the hydropathy scale for amino acid side chains in Table A2. Table A1 - Chemical properties of amino acids Ala (A) alifático, hidróphobo, neutro Met (M) hidróphobo, neutro Cys (C) polar, hidróphobo, neutro Asn (N) polar, hidrófilo, neutro Asp (D) polar, hidrófilo, chargedo (-) Pro (P) hidróphobo, neutro Glu (E) polar, hidrófilo, chargedo (-) Gln (Q) polar, hidrófilo, neutro Phe (F) aromatic, hidróphobo, neutro Arg (R) polar, hidrófilo, charged (+) Gly (G) alifático, neutro Ser (S) polar, hidrófilo, neutro His (H) aromatic, polar, hidrófilo, loaded (+) Thr (T) polar, hidrófilo, neutro Lle(L) alifático, hidróphobo, neutro Val (V) alifático, hidróphobo, neutro Lys (K) polar, hidrófilo, loaded (+) Trp (W) aromatic, hidróphobo, neutro Leu (L) alifático, hidróphobo, neutro Tyr (Y) aromatic, polar, hidróphobo 10 Table A2 - Scale of Hydropathy Chain Lateral Hydropathy He 4,5 Val 4,2 Leu 3,8 Phe 2,8 Cys 2,5 Met 1,9 Ala 1,8 Gly 0,4 Thr -0,7 Ser -0,8 Trp -0,9 Tyr -1,3 Pro -1,6 His -3,2 Glu -3,5 Gln -3,5 Asp -3,5 Asn -3,5 Lys -3,9 Arg -4,5 Lbfrrnn / Lznz / e / YiAi In any polypeptide disclosed herein, one or more of the following modifications may be made to improve the physicochemical properties 5 (e.g., stability), provided that the polypeptide exhibits the same or greater immunogenicity for arginase 1, compared to a polypeptide having the unmodified sequence: a) replacement of the C-terminal amino acid with the corresponding amide (may increase resistance to carboxypeptidases); b) replacement of the N-terminal amino acid with the corresponding acylated amino acid (may increase resistance to aminopeptidases); c) replacement of one or more amino acids with the corresponding methylated amino acids (may improve proteolytic resistance); Lbfrrnn / Lznz / e / YiAi d) replacement of one or more amino acids with the corresponding amino acid in the D configuration (may improve proteolytic resistance). For modifications of types (c) and (d), a preferred example is the modification of the Tyr moiety at the position corresponding to position 29 of SEQ ID NO: 1 (e.g., replacing with N-methyl(Tyr) or replacing with Tyr in the D configuration). This is because Tyr appears immediately after a Lys moiety at position 28 and is therefore at a potential site for proteolysis by trypsin-like proteases (which normally cleave after Lys). Any polypeptide disclosed herein may have at least one additional residue attached at the N and / or C end to improve solubility, stability, and / or to aid in manufacturing / isolation, provided that the polypeptide exhibits the same or greater immunogenicity for arginase 1 compared to a polypeptide lacking the additional residue. Suitable residues include hydrophilic amino acids. For example, the amino acid sequences KK, KR, or RR may be added at the N and / or C end. Other suitable residues include albumin or PEG (polyethylene glycol). A polypeptide as disclosed herein can be produced by any suitable means. For example, the polypeptide can be synthesized directly using conventional techniques known in the art, such as Fmoc solid-phase chemistry, Boc solid-phase chemistry, or by solution-phase peptide synthesis. Alternatively, a polypeptide can be produced by transforming a cell, typically a bacterial cell, with a nucleic acid molecule or a vector encoding the polypeptide. The invention provides nucleic acid molecules and vectors encoding a polypeptide of the invention. The invention also provides a host cell comprising the nucleic acid or vector. The terms nucleic acid molecule and polynucleotide are used interchangeably herein and refer to a polymeric form of nucleotides of any length, whether deoxyribonucleotides, ribonucleotides, or analogues thereof. Non-limiting examples of polynucleotides include a gene, a gene fragment, messenger RNA (mRNA), cDNA, recombinant polynucleotides, plasmids, vectors, DNA isolated from any sequence, RNA isolated from any sequence, nucleic acid probes, and primers. A polynucleotide of the invention may be provided in isolated or substantially isolated form. By substantially isolated, it is understood that there may be substantial isolation, but not Lbfrrnn / Lznz / e / YiAi total, of the polypeptide from any surrounding medium. The polynucleotides may be mixed with carriers or diluents that do not interfere with their intended use and still be considered substantially isolated. A nucleic acid sequence “coding” a selected polypeptide is a nucleic acid molecule that is transcribed (in the case of DNA) and translated (in the case of mRNA) into a polypeptide in vivo when placed under the control of appropriate regulatory sequences, for example, in an expression vector. The boundaries of the coding sequence are determined by a start codon at the 5' (amino) end and a translation stop codon at the 3' (carboxy) end. For the purposes of the invention, such nucleic acid sequences may include, but are not limited to, cDNA from viral, prokaryotic, or eukaryotic mRNA, viral or prokaryotic DNA or RNA genomic sequences, and even synthetic DNA sequences.A transcription termination sequence can be located 3' from the coding sequence. Polynucleotides can be synthesized according to methods well known in the art, as described by way of example in Sambrook et al. (1989, Molecular Cloning - a laboratory manual; Coid, Spring Harbor Press). The nucleic acid molecules of the present invention can be provided in the form of an expression cassette that includes control sequences operatively linked to the inserted sequence, thereby enabling in vivo expression of the antibody of the invention. These expression cassettes are, in turn, typically provided within vectors (e.g., recombinant plasmid or viral vectors). Such an expression cassette can be administered directly to a host subject. Alternatively, a vector comprising a polynucleotide of the invention can be administered to a host subject. Preferably, the polynucleotide is prepared and / or administered using a genetic vector.A suitable vector can be any vector that is capable of carrying a sufficient amount of genetic information and allowing the expression of a polypeptide of the invention. Therefore, the present invention includes expression vectors comprising said polynucleotide sequences. Such expression vectors are routinely constructed in molecular biology techniques and may involve, for example, the use of plasmid DNA and appropriate primers, promoters, enhancers, and other elements, such as polyadenylation signals, which may be required and positioned in the correct orientation to enable the expression of a peptide of the invention. Other suitable vectors will become apparent to the Lbfrrnn / Lznz / e / YiAi experts in the field. As a further example in this regard, reference is made to Sambrook et al. The invention also includes cells that have been modified to express a polypeptide of the invention. Such cells typically include prokaryotic cells such as bacterial cells, for example, E. coli. These cells can be cultured using conventional methods to produce a polypeptide of the invention. The polypeptide of the invention may be in a substantially isolated form. It may be mixed with carriers, preservatives, or diluents (discussed below) that will not interfere with the intended use, and / or with an adjuvant (also discussed below), and will still be considered as substantially isolated. It may also be in a substantially purified form, in which case it will generally comprise at least 90%, for example, at least 95%, 98%, or 99% of the protein in the preparation. Compositions comprising polypeptides or polynucleotides In another aspect, the present invention provides a composition comprising a polypeptide of the invention. The present invention also provides a composition comprising a polynucleotide encoding a polypeptide of the invention. For example, the invention provides a composition comprising one or more polypeptides of the invention and at least one pharmaceutically acceptable carrier, preservative, or excipient. Alternatively, the invention provides a composition comprising one or more polynucleotides encoding a polypeptide of the invention and at least one pharmaceutically acceptable carrier, preservative, or excipient. The carrier, preservative, and excipient must be acceptable in the sense of being compatible with the other ingredients of the composition and not harmful to a subject to whom the composition is administered. Typically, all components and the final composition are sterile and pyrogenic.The composition may be a pharmaceutical composition. The composition may preferably include an adjuvant. Adjuvants are any substances whose mixture in the composition enhances or otherwise modifies the immune response elicited by the composition. Broadly defined, adjuvants are substances that promote an immune response. Adjuvants may also preferentially have a depot effect, as they result in a slow and sustained release of an active agent from the site of administration. A general analysis is provided of Lbfrrnn / Lznz / e / YiAi adjuvants in Goding, Monoclonal Antibodies: Principles & Practice (2nd edition, 1986) on pages 61-63. The adjuvants can be selected from the group consisting of: AIK(SO4)2, AINa(SO4)2, AINH4 (SO4), silica, alum, AI(OH)3, Ca3 (PO4)2, kaolin, carbon, aluminum hydroxide, muramyl dipeptides, N-acetyl-muramyl-L-treoglumine (thr-DMP), N-acetyl-nornuramyl-L-alanyl-D-isoglutamine (CGP 11687, also named nor-MDP), N-acetylmuramiul-L-alanyl-D-isoglutaminyl-L-alanine-2-(Γ2'dipalmitoyl-sn-3-hydroxyphosphoryl) -ethylamine (CGP 19835A, also referred to as MTP-PE), RIBI (MPL+TDM+CWS) in a 2 % squalene emulsion / Tween80.RTM.Lipopolysaccharides and their various derivatives, including lipid A, Freund's complete adjuvant (FCA), Freund's incomplete adjuvants, Merck adjuvant 65, polynucleotides (e.g., poly IC and poly AU acids), Mycobacterium tuberculosis wax D, substances found in Corynebacterium parvum, Bordetella pertussis, or members of the genus Brucella), Titermax, ISCOMS, Quil A, ALUN (see US documents 58767 and 5,554,372), lipid A derivatives, choleratoxin derivatives, HSP derivatives, LPS derivatives, synthetic peptide or GMDP arrays, interleukin 1, interleukin 2, Montanide ISA-51, and QS-21. Various saponin extracts have also been suggested as useful as adjuvants in immunogenic compositions. Granulocyte-macrophage colony-stimulating factor (GM-CSF) can also be used as an adjuvant. Preferred adjuvants for use with the invention include oil / surfactant-based adjuvants such as Montanide adjuvants (available from Seppic, Belgium), preferably Montanide ISA-51. Other preferred adjuvants are bacterial DNA-based adjuvants, such as adjuvants containing CpG oligonucleotide sequences. Still other preferred adjuvants are viral dsRNA-based adjuvants, such as poly l:C. GM-CSF and imidazoquinolines are also examples of preferred adjuvants. The adjuvant is most preferably a Montanide ISA adjuvant. The Montanide ISA adjuvant is preferably Montanide ISA 51 or Montanide ISA 720. In Goding, Monoclonal Antibodies: Principles & Practice (2nd edition, 1986), on pages 61-63, it is also noted that when an antigen of interest is of low molecular weight or poorly immunogenic, coupling to an immunogenic carrier is recommended. Therefore, a polypeptide of the invention can be coupled to a carrier. A carrier can be present independently of a Lbfrrnn / Lznz / e / YiAi adjuvant. The function of a transporter can be, for example, to increase the molecular weight of a polypeptide fragment to enhance its activity or immunogenicity, confer stability, increase biological activity, or extend its serum half-life. A transporter can also help present the polypeptide or its fragment to T lymphocytes. Therefore, in its composition, the polypeptide may be associated with a transporter such as those described below. The transporter can be any suitable transporter known to a person skilled in the art, for example, a protein or an antigen-presenting cell, such as a dendritic cell (DC). Transport proteins include hemocyanin from the California limpet, serum proteins such as transferrin, bovine serum albumin, human serum albumin, thyroglobulin, or ovalbumin, immunoglobulins, or hormones such as insulin or palmitic acid. Alternatively, the transport protein can be tetanus toxoid or diphtheria toxoid. Alternatively, the transporter can be a dextran such as sepharose. The transporter must be physiologically acceptable to humans and safe. If the composition includes an excipient, the excipient must be pharmaceutically acceptable, meaning it is compatible with the other ingredients of the composition and not harmful to the recipient. Excipients may include auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and the like. These excipients and auxiliary substances are generally pharmaceutical agents that do not induce an immune response in the individual receiving the composition and can be administered without undue toxicity.Pharmaceutically acceptable excipients include, but are not limited to, liquids such as water, saline solution, polyethylene glycol, hyaluronic acid, glycerol, and ethanol. Also included are pharmaceutically acceptable salts, for example, salts of mineral acids, such as hydrochlorides, hydrobroms, phosphates, sulfates, and the like; and salts of organic acids, such as acetates, propionates, malonates, benzoates, and the like. A comprehensive analysis of pharmaceutically acceptable excipients, vehicles, and excipients is available from Remington's Pharmaceutical Sciences (Mack Pub. Co., NJ 1991). The formulation of a suitable composition can be carried out using conventional chemical processes and pharmaceutical formulation methodologies, all of which are readily available to the skilled practitioner. Such compositions can then be prepared, packaged, or marketed in a form suitable for administration. Lbfrrnn / Lznz / e / YiAi for bolus or continuous administration. Injectable compositions may be prepared, packaged, or marketed in unit-dose form, such as in ampoules or multidose containers, optionally containing a preservative. Compositions include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and sustained-release or biodegradable implantable formulations. In one embodiment of a composition, the active ingredient is provided in dry form (e.g., a powder or granules) for reconstitution with a suitable vehicle (e.g., sterile, pyrogen-free water) prior to administration of the reconstituted composition. The composition may be prepared, packaged, or marketed as a sterile injectable aqueous or oily suspension or solution.This suspension or solution may be formulated according to known art and may comprise, in addition to the active ingredient, additional ingredients such as the adjuvants, excipients, and auxiliary substances described herein. Such sterile injectable formulations may be prepared using a parenterally acceptable, non-toxic diluent or solvent, such as water or 1,3-butanediol, for example. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or diglycerides. Other useful compositions include those comprising the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer system.Compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion-exchange resin, a sparingly soluble polymer, or a sparingly soluble salt. Alternatively, the active ingredients of the composition may be encapsulated, adsorbed, or associated with particulate carriers. Suitable particulate carriers include polymethyl methacrylate polymer derivatives, as well as PLG microparticles derived from poly(lactides) and poly(lactide-co-glycolides). See, e.g., Jeffery et al. (1993) Pharm. Res. 10:362-368. Other particulate systems and polymers may also be used, for example, polymers such as polylysine, polyarginine, polyornithine, spermine, spermidine, as well as conjugates of these molecules. Methods of use The polypeptide, polynucleotide, or composition of the invention may be used in a method for treating or preventing a disease or condition in a subject. The polypeptide, polynucleotide, or composition of the invention may be used in the manufacture of a Lbfrrnn / Lznz / e / YiAi medicament for use in a method for treating or preventing a disease or condition in a subject. The method comprises administering to said subject the said polypeptide, the said polynucleotide, or the said composition. The administration may be of a therapeutically or prophylactically effective amount of said polypeptide, the said polynucleotide, or the said composition to a subject in need. The disease or condition may be characterized, at least in part, by inappropriate or excessive arginase-1 immunosuppressive function. The disease or condition may be a cancer, preferably a cancer that expresses arginase-1 and / or is associated with inappropriate or excessive arginase-1 immunosuppressive function. The cancer may be breast, lung, or prostate cancer, or it may be a leukemia, preferably acute myeloid leukemia (AML), or it may be a melanoma. The method may involve simultaneous or sequential administration with an additional cancer therapy. The additional cancer therapy may be selected from cytokine therapy, T-cell therapy, NK cell therapy, an immune checkpoint inhibitor, chemotherapy, radiotherapy, immunostimulatory substances, gene therapy, or an antibody. The antibody can be abagovomab, abciximab, actoxumab, adalimumab, adecatumumab, afelimomab, afutuzumab, alacizumab pegol, ALD518, alemtuzumab, alirocumab, altumomab pentetate, amatuximab, anatumomab, maruknatoxumab, apolizumab, apolizumab arcitumomab, acelizumab, atinumab, atlizumab (= tocilizumab), atorolimumab, bapineuzumab, basiliximab, bavituximab, bectumomab, belimumab, benralizumab, bertilimumab, becilesomab, bevacizumab, bezlotoxumab, biciromumab, bimarumab, bimervacine, mervacina blinatumomab, blosozumab, brentuximab vedotina, briakinumab, brodalumab, canakinumab, cantuzumab mertansina, cantuzumab ravansina, caplacizumab, capromab pendetida, carlumab, catumaxomab, CC49, cedelizumab, certolizumab pegol, cetuximab, Ch.18, citatuzumab bogatox, cixutumumab, clazakizumab, clenoliximab, clivatuzumab tetraxetan, conatumumab, concizumab, crenezumab, CR6261, dacetuzumab, daclizumab, dalotuzumab, daratumumab, demcizumab, decituzumab, detumomab, dorsumumab aritox, drozitumab, duligotumab, dupilumab, dusigitumab, ecromeximab, eculizumab, edobacomab, edrecolomab, efalizumab, efungumab, elotuzumab elsilimomab, enavatuzumab, enlimomab pegol, enokizumab, enoticumab, ensitumab, cituxemab, cituxetine epratuzumab, erlizumab, ertumaxomab, etaracizumab, etrolizumab, evolocumab, exbivirumab, fanolesomab, faralimomab farletuzumab, fasinumab, FBTA05, felvizumab,. Lbfrrnn / Lznz / e / YiAi fezakinumab, ficlatuzumab, figitumumab, flanvotumab, fontolizumab, foralumab, foravirumab, fresolimumab, fulranumab, futuximab, galiximab, ganitumab, gantenezumab, gezokitumicimomab girentuximab, glembatumumab vedotina, golimumab, gomiliximab, GS6624, ibalizumab, ibritumumab tiuxetan, icrucumab, igovomab, imciromab, imgatuzumab, inclacumab, indatulimomab ravtansina, intetum oinflizomib, inobximab, ipilimumab, iratumumab, itolizumab, ixekizumab, keliximab, labetuzumab, lampalizumab, lebrikizumab, lemalesomab, lerdelimumab, lexatumumab, libivirumab, gegelizumab, lintuzumab, lirilumzub, loca mertamezumab lumiliximab, matatumumab, maslimomab, mavrilimumab, matuzumab, mepolizumab, metelimumab, milatuzumab, minretumumab, mitumumab, mogamulizumab, morolimumab, motavizumab, moxetumumab pasudotox, muromox, nacolopmab-CD3, stafenatox, narnatumab,natalizumab, nebacumab, necitumumab, nerilimomab, nesvacumab, nimotuzumab, nivolumab, nofetumomab merpentano, obinutuzumab, ocaratuzumab, ocrelizumab, odulimomab, ofatumumab, olaratumab, olokizumab, omalizumab, onartuzumab, monoportuzumab, monoportuzumab oregovomab, orticumab, otelixizumab, oxelumab, ozanezumab, ozoralizumab, pagibaximab, palivizumab, panitumumab, panobacumab, parsatuzumab, pascolizumab, pateclizumab, patritumab, pemtumomab, perakizumab, pertulizumab, pexelizumab, pixelizumab, pinatuzumab vedotina, pintumomab, placulumab, polatuzumab vedotina, ponezumab, priliximab, pritoxaximab, pritumumab, PRO 140, quilizumab, racotumomab, radretumab, rafivirumab, ramucirumab, ranibizumab, raxibacumab, regalumab, reslotumab, reslotumab, rituximab, robatumumab, roledumab, romosozumab, rontalizumab, rovelizumab, ruplizumab, samalizumab, sarilumab, satumomab pendetida, secukinumab, seribantumab, cetoxaximab, sevirumab, sibrotuzumab, cefalimumab, siltuximab, simplizumab, simplizumab sirukumab,solanezumab, solitomab, sonepcizumab, sontuzumab, stamulumab, sulesomab, suvizumab, tabalumab, tacatuzumab tetraxetano, tadocizumab, talizumab, tanezumab, taplitumomab paptox, tefibazumab, telimomab aritox, telizumab, telizumab, teplizumab teprotumumab, TGN1412, ticilimumab (= tremelimumab), tildrakizumab, tigatuzumab, TNX-650, tocilizumab (= atlizumab), toralizumab, tositumomab, tralokinumab, trastuzumab, TRBS07, tregalizumab, tremelimumab, tumovicine, tumor cells ublituximab, urelumab, urtoxazumab, ustekinumab, vapaliximab, vatelizumab, vedolizumab, veltuzumab, vepalimomab vezincumab, visilizumab, volociximab, vorsetuzumab mafodotina, Lbfrrnn / Lznz / e / YiAi votumumab, zalutumumab, zanolimumab, zatuximab, ziralimumab and zolimomab aritox. Preferred antibodies include natalizumab, vedolizumab, belimumab, atacicept, alefacept, otelixizumab, teplizumab, rituximab, ofatumumab, ocrelizumab, epratuzumab, alemtuzumab, abatacept, eculizumab, omalizumab, canakinumab, melizumab, resplizumab, tocilizumab, ustekinumab, briakinumab, etanercept, infliximab, adalimumab,, certolizumab pegol, golimumab, trastuzumab, gemtuzumab, ozogamycin, ibritumomab, tiuxetan, tostitumomab, cetuximab, bevacizumab, panitumumab, panitumumab, ipilimumab, ipilimumab, vedotin. Particularly preferred antibodies that may be used in the method of the invention include: daratumumab, nivolumab, pembrolizumab, avelumab, rituximab, trastuzumab, pertuzumab, alemtuzumab, cetuximab, panitumumab, tositumomab and ofatumumab. Daratumumab is especially preferred. Additional cancer therapy may be selected from the group consisting of actimide, azacitidine, azathioprine, bleomycin, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxyfluridine, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxyurea, idarubicin, irinotecan, lenalidomide, leucovorin, mechlorethamine, melphalan, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, revlimid, temozolomide, teniposide, thioguanine, valrubicin, vinblastine, vincristine, vindesine, and vinorelbine. The polypeptide or composition of the invention can also be used in a method for stimulating arginase-1-specific T lymphocytes, such as CD4 and CD8 T lymphocytes, comprising contacting the cells with said polypeptide or composition. The method can be carried out ex vivo. The cells can be present in a sample taken from a healthy subject or from a cancer patient, such as in a tumor sample. The present invention is further illustrated by the following examples, which, however, should not be interpreted as limiting the scope of protection. The features disclosed in the preceding description and in the following examples may, individually or in any combination thereof, be essential to carrying out the invention in various forms thereof. Lbfrrnn / Lznz / e / YiAi Example 1 Materials and methods Patient materials PBMCs were isolated from healthy donors using density gradient separation on Lymphoprep™ (STEMCELL Technologies) and cryopreserved at 150 °C in FBS supplemented with 10% DMSO. PBMCs from cancer patients were isolated from a blood sample at least four weeks after completion of any cancer therapy. The Scientific Ethics Committee for the Capital Region of Denmark approved the protocol, and it was conducted in accordance with the provisions of the Declaration of Helsinki. Written informed consent was obtained from patients prior to enrollment in the study. Peptides The peptides were synthesized using conventional methods and provided dissolved in DMSO to a standard concentration of 10 mM. The sequences of the peptides used in these experiments are shown in full below in alignment with each other and are also discussed in the section titled Sequences. The peptides are described by SEQ ID NO, by name, or by reference to the start and end positions of each peptide sequence within the full-length arginase 1 sequence. Each may be used interchangeably. For example, the peptide of SEQ ID NO: 1 may alternatively be called ArgLong2, or alternatively, Arg169-206 (given a start position of 169 and a stop position of 206). The intended reference in each case will be clear from the context. Longer peptide sequences: ArgLong: ISAKDIVYIGLRDVDPGEHYILKTLGIKYFSMTEVDRLGIGK ArgLong2: ISAKDIVYIGLRDVDPGEHYILKTLGIKYFSMTEVDRL ArgLong3: ISAKDIVYIGLRDVDPGEHYILKTLGIKYFSM 20-mer peptides: Argi7i-i90: AKDIVYIGLRDVDPGEHYIL Argi8i.2oo: DVDPGEHYILKTLGIKYFSM Argi9i-2i0: KTLGIKYFSMTEVDRLGIGK ELISPOT Trial For ELISPOT in vitro, PBMCs from cancer patients and healthy donors were pulsed with 20 μM of arginase-1-derived peptides and 120 U / ml of IL-2 in plates of Lbfrrnn / Lznz / e / YiAi cells were incubated for 7 days before use in an ELISPOT assay. Cells were seeded in 96-well nitrocellulose ELISPOT plates (MultiScreen MAIP N45; Millipore) pre-coated with IFNγ capture antibody (Mabtech). Arginase peptides were added to a final concentration of 5 μM, and the plates were incubated at 37 °C for 14–16 hours. After incubation, the cells were washed, and biotinylated secondary antibody (Mabtech, cat. 3420-6-1000) was added for 2 hours at room temperature. Unbound secondary antibody was removed by washing, and streptavidin-conjugated alkaline phosphatase (AP) (Mabtech, cat. 3310-10) was added for 1 hour at room temperature. The unbound conjugated enzyme was removed by washing and the assay was developed by adding substrate BCIP / NBT (Mabtech, cat. 3650-10).The developed ELISPOT plates were analyzed on the CTL ImmunoSpot S6 Ultimate-V analyzer using the Immunospot v5.1 software program. Responses were reported as the difference between the mean number of spots in the arginase 1 stimulated wells and the wells without added peptide. To test Arg1 responses induced by IL-4, PBMCs were stimulated with IL-4 (100 or 50 U / ml) and / or IL-2 (120 or 60 U / ml) for one week prior to preparation for the ELISPOT assay as described above. Intracellular staining Intracellular staining of cell cultures was performed after stimulating PBMCs with arginase-derived peptides for 5 hours in the presence of BD GolgiPlug™ (added after the first hour of peptide stimulation). Stimulated cells were stained with fluorescently labeled antibodies for surface markers (CD3, CD4, CD8) and subsequently permeabilized using fixation / permeabilization buffer and permeabilization (eBioscience, cat. 00-5123-43), according to the manufacturer's instructions. Permeabilized cells were then stained with fluorochrome-labeled antibodies for IFNγ and TNFα. Flow cytometry analysis was performed on a FACSCanto™ II (BD Biosciences). Antibodies used: IFNy-APC (cat.341117), TNFa-455 BV421 (cat.562783), CD4-FITC (cat.347413), CD8-PerCP (cat.345774), CD3-APC-H7 (cat.560275) (all from BD Biosciences), dead cell staining-FVS510 (564406, BD Biosciences) according to the manufacturer's instructions. Memory T lymphocyte sorting. CD4+ and CD8+ memory T lymphocytes were classified from samples of Lbfrrnn / Lznz / e / YiAi Freshly thawed primary cellular monoclonal antibodies (PBMCs) from healthy donors or cancer patients were sorted using magnetic bead sorting kits: CD4+ Memory T Cell Isolation Kit, Human (cat. 130-091-893, Miltenyi Biotec) and CD8+ Memory T Cell Isolation Kit, Human (cat. 130-094-412, Miltenyi Biotec). The purity of the isolated cells was assessed by staining for CD4-FITC, CD8-PerCP, and CD45RO-PE (all from BD Biosciences). Dead cells were stained using the LIVE / DEAD™ Fixable Near-IR Dead Cell Staining Kit (Invitrogen™, ThermoFisher Scientific). Results The length of arginase peptide 1 determines the effectiveness of T lymphocyte stimulation Based on the previously identified 50-amino-acid Arg1 hotspot region at positions 161–210 of arginase 1, three different peptides were selected that covered most of this region while also excluding cysteine ​​at position 168 of arginase 1 (expected to improve manufacturability, solubility, and stability). The three peptides were: 42-mer ArgLong (positions 169–210), 38-mer ArgLong2 (positions 169–206), and 32-mer ArgLong3 (positions 169–200). To test whether these peptides could be used to identify arginase-1 responses, primary bioproliferative corneas (PBMCs) from six healthy donors were explored to determine responses to IFN-γ ELISPOT. PBMCs were stimulated with the ArgLong2 peptide and low doses of IL-2 for one week prior to ELISPOT. Despite sequence similarities, the ArgLong2 peptide appeared to be superior in stimulating T cell responses to IFN-γ ELISPOT. As shown in Figure 1, high responses against the ArgLong2 peptide were observed in four of the six donors, while there were low or no responses against the ArgLong and ArgLong3 peptides. ArgLong2 is only 4 amino acids shorter than ArgLong and 6 amino acids longer than ArgLong3. This suggests that peptide length and sequence may play a crucial role in ensuring optimal processing and presentation of arginase peptides. Consequently, it may affect the ability of these peptides to activate Arg1-specific T lymphocytes. To determine whether the ArgLong2 peptide is comparable to the previously described 20-mer single-strand peptides covering the same sequence (see examples 1, 2, and 3 in WO2018065563), PBMCs from 19 healthy donors and 16 cancer patients (8 with melanoma, 6 with multiple myeloma, 1 with cancer) were screened. Lbfrrnn / Lznz / e / YiAi (breast cancer) and 1 (renal cell carcinoma) were used to determine responses against three 20-mer peptides and the 38-mer peptide ArgLong2. In both cancer patients and healthy donors, ArgLong2 elicited the most responses compared to the three 20-mer peptides (see Figure 2). Strong responses against ArgLong2 were observed in 14 of 19 healthy donors and 8 of 16 cancer patients. Responses against the 20-mer peptides were also observed, although they were fewer and weaker. In summary: Argni-wo showed responses in 3 healthy donors and 3 cancer patients, Argi8i-2oo showed responses in 4 healthy donors and 6 cancer patients, and Argi91.2io showed responses in 7 healthy donors and 3 cancer patients. Responses against arginase 1 of CD4+ and CD8+ lymphocytes The T cell responses described above against 20-mer Arg1 peptides have shown predominantly CD4+ T cell responses in cancer patients and healthy donors (see example 2 in WO2018065563). Because the ArgLong2 peptide appeared to be more efficiently processed and subsequently recognized by T cells, the type of T cell responses to ArgLong2 was investigated using intracellular staining. Breast-cell monoclonal antibodies (BCMAs) from two healthy donors (HD384, HD400) and one breast cancer patient (BD30), which had previously shown strong responses against ArgLong2 in ELISPOT, were tested by intracellular staining one week after stimulation with ArgLong2 and low doses of IL-2 in vitro. Notably, both CD4+ and CD8+ T cell responses against the ArgLong2 peptide were identified in the cancer patient and the healthy donors. Both CD4+ (left panel of Figure 3A) and CD8+ (right panel of Figure 3A) responses were detected in the BCMAs of one healthy donor and the breast cancer patient. The other healthy donor showed only a CD8+ T cell response. Interestingly, detectable CD4+ and CD8+ responses against ArgLong2 were also observed in intracellular staining of PBMCs without prior peptide stimulation. PBMCs from two cancer patients (one malignant melanoma (MM27) and one breast cancer (BC30)) were thawed and directly tested for ArgLong2 peptide responses in ex vivo intracellular staining. Ex vivo CD4+ responses were detected in PBMCs from both cancer patients (Figure 3B, left), and ex vivo CD8+ responses were detected in PBMCs from the breast cancer patient (Figure 3B, right). Responses against arginase 1 of CD4+ and CD8+ memory lymphocytes Lbfrrnn / Lznz / e / YiAi The strong responses observed against ArgLong2 indicated that Arg1-specific T cell frequencies could be more commonly detected in PBMCs without any prior peptide stimulation. PBMCs from 4 healthy donors and 2 cancer patients (1 breast cancer and 1 malignant melanoma) that had shown strong responses in in vitro ELISPOT were directly tested to determine responses to the ArgLong2 peptide in ex vivo IFNγ ELISPOT. Significant spontaneous responses were found in all 6 donors (see Figure 4A). The presence of strong spontaneous ex vivo responses against the ArgLong2 peptide in PBMCs from healthy donors and cancer patients suggested that arginase-1-specific cells are a natural part of the immune system. To test this, CD4+ and CD8+ memory T cells were sorted from PBMCs of cancer patients and healthy donors that had shown a strong spontaneous ex vivo immune response. CD4+ or CD8+ memory T cells were sorted from PBMCs of 4 healthy donors and 2 cancer patients using magnetic bead sorting and configured in an ex vivo IFNγ ELISPOT. The purity of the memory T cell isolate was confirmed by flow cytometry analysis for CD4+CD45RO+ and CD8+CD45RO+ T cells and was determined to be >95%. CD4+ memory T cell responses against the ArgLong2 peptide were found in 2 cancer patients and 3 healthy donors (see Figure 4B).Clear CD8+ memory T lymphocyte responses were detected in 2 healthy donors (see Figure 4C). IL-4-upregulated arginase 1 expression increases T cell responses against ArgLong2 Because Arg1-specific CD4+ and CD8+ memory T cells are present in both cancer patients and healthy donors, we investigated whether these T cells might be involved in immune regulation in response to upregulated Arg1 expression. Arg1 has been previously described as being upregulated in myeloid cells in response to IL-4. First, PBMCs from a single melanoma patient that had previously demonstrated a strong spontaneous response against the ArgLong2 peptide ex vivo were tested. The PBMCs were thawed and stimulated with IL-4 (50 U / ml or 100 U / ml), IL-2 (120 U / ml), or a combination of IL-4 and IL-2 (50 U / ml and 60 U / ml, respectively) for one week before being tested on an IFNγ ELISPOT to determine responses against ArgLong2. Unstimulated cells were used as Lbfrrnn / Lznz / e / YiAi control. Strong, significant responses were observed in all IL-4-stimulated groups: the highest responses were observed against the IL-4-stimulated groups compared to no stimulation or IL-2-only stimulation, suggesting that Arg1-specific T lymphocytes are activated in response to upregulated Arg1 expression. See Figure 5A. PBMCs from two cancer patients (BC30 (breast cancer), MM27 (malignant melanoma)) and six healthy donors who had previously shown strong spontaneous responses against ArgLong2 ex vivo were stimulated with low doses of IL-2 (120 U / ml) or IL-4 (100 U / ml) for 7 days. Unstimulated cells were used as a control. After 7 days in culture, PBMC reactivity against ArgLong2 was tested using IFNγ ELISPOT. Six of eight cultures showed increased responses against ArgLong2 in IL-4-stimulated cultures compared to unstimulated and IL-2-stimulated controls, further confirming the possible common mechanism of Arg1-specific T cell activation in vivo. See Figure 5B. Analysis The existence of Arg1-specific T lymphocytes has been previously described. These T lymphocytes can be termed anti-Treg due to their role in targeting immune regulatory proteins. Anti-Treg responses against other immune regulatory proteins, such as PD-L1 and IDO, have also been described. Previous experiments demonstrate that arginase 1-specific anti-Tregs are not only spontaneously present in cancer patients and healthy donors, but also exist as part of the memory T cell repertoire, as responses against the ArgLong2 peptide were observed in isolated populations of CD4+ and CD8+ memory T lymphocytes. To maintain immune balance, regulatory immune cells, such as Tregs, various dendritic cell subtypes, myeloid-derived suppressor cells, and M2 macrophages, suppress or terminate immune responses. This regulatory group ensures a lack of response or tolerance to self-antigens. Regulatory immune cells suppress immunity through various cellular and extracellular factors. In contrast, specific anti-Tregs that recognize HLA-restricted epitopes derived from degraded intracellular antigens are able to directly eliminate regulatory immune cells. Furthermore, anti-Tregs can enhance local immune activation by secreting effector cytokines. Lbfrrnn / Lznz / e / YiAi Th2-driven pulmonary inflammation increases arginase-1 expression on myeloid cells. In particular, IL-4, the prototypical inducer of the M2 macrophage phenotype, induced the upregulation of arginase-1. In this case, arginase-1-specific T lymphocytes were shown to be activated in response to the Th2 cytokine IL-4. Consequently, this suggests that arginase-1-specific Th1 lymphocytes infiltrate environments with increased IL-4 and drive the immune response back toward the Th1 pathway, which could be an important role for arginase-1-specific anti-Tregs in controlling immune inhibition and promoting inflammation. However, arginase-1-specific anti-Tregs are hampered by the suppressive effects of arginase-1-expressing regulatory immune cells.Therefore, in immune regulatory networks, arginase-1-specific anti-Tregs suppress the function of arginase-1+ regulatory immune cells, and vice versa. Consequently, under normal physiological conditions, a balance between immune activation and suppression may be necessary to maintain immune homeostasis. The findings of arginase-1-specific memory T cells in healthy individuals, which expand in response to IL-4, are consistent with previous findings regarding IDO- and PD-L1-specific anti-Tregs. Circulating IDO- or PD-L1-specific anti-Tregs have been identified in healthy donors, although their detection was not as frequent as in cancer patients. Additionally, the proinflammatory cytokines IL-2 and IFN-γ, which are known to induce IDO and PD-L1, have been found to expand IDO- or PD-L1-specific T cell populations among human PBMCs without further stimulation. The expression of arginase 1 in the tumor microenvironment by immunosuppressive myeloid cells inhibits antitumor T cell responses through L-arginine depletion. In an arginase 1-positive environment, T cells cannot proliferate, and therefore, a promising therapeutic strategy is to reconstitute adaptive immune responses by activating arginase 1-specific pro-inflammatory T cells. Activation of arginase 1-specific anti-Tregs by peptide vaccination offers a novel approach to targeting a specific immune inhibitory mechanism in cancer. The development of new immunotherapeutic approaches in cancer treatment is likely to be more effective and versatile when they target common suppressive mechanisms, as shown in these experiments. Arginase-1-specific anti-Tregs exist as a natural part of the immune system and can be employed Lbfrrnn / Lznz / e / YiAi easily to tip the balance away from immune suppression in cancer. The peptide ArgLong2, which covers most of the arginase 1 hotspot region described above, has been shown to be particularly effective at stimulating arginase-specific CD4+ and CD8+ T lymphocyte responses compared to similar peptides of different lengths. ArgLong2, therefore, has a particularly high probability of success in a vaccination setting, given its potential to stimulate arginase 1-specific anti-Tregs that can exert both effector and auxiliary functions in the tumor microenvironment. Example 2 - Design of additional peptides In order to design peptides suitable for use in mouse vaccination experiments, and which may also be functional in humans, the murine arginase 1 sequence (SEQ ID NO: 11) was compared with the human arginase 1 sequence from SEQ ID NO: 10. The level of similarity is particularly high in the human arginase 1 hotspot region corresponding to positions 161-210 of SEQ ID NO: 1. An alignment of this region and the corresponding region in murine arginase 1 is also shown below: hArgl: GFSWVTPCISAKDIVYIGLRDVDPGEHYILKTLGIKYFSMTEVDRLGIGK (SEQ ID NO: 12) mArgl: GFSWVTPCISAKDIVYIGLRDVDPGEHYIIKTLGIKYFSMTEVDKLGIGK (SEQ ID NO: 13) Only two of the 50 residues differ, shown in bold and underlined. A leucine in the human sequence is substituted by the very similar aliphatic amino acid isoleucine in the mouse, and an arginine in the human sequence is similarly substituted by basic lysine in the mouse. Both changes are conservative. Consequently, the hotspot region is highly conserved between humans and mice. Therefore, the polypeptides of the invention include polypeptides consisting of a particular human sequence from the hotspot region, but in which the substitutions of the corresponding mouse sequence are made. For example, SEQ ID NO: 2 corresponds to SEQ ID NO: 1 but with the aforementioned leucine-isoleucine and arginine-lysine substitutions. The polypeptide consisting of SEQ ID NO: 2 may be referred to herein as mArgLong2.Similarly, SEQ ID NO: 4 corresponds to SEQ ID NO: 3 but with the leucine-isoleucine substitution mentioned above. The polypeptide consisting of SEQ ID. Lbfrrnn / Lznz / e / YiAi SEQ ID NO: 2 may be referred to herein as mArgLong3. Similarly, SEQ ID NO: 6 corresponds to SEQ ID NO: 5 but with the leucine-isoleucine and arginine-lysine substitutions mentioned above. The polypeptide consisting of SEQ ID NO: 6 may be referred to herein as mArgLong. The murine peptides are expected to have similar potential as vaccines to their human counterparts. Example 3 - In vivo experiments with human ArqLonq2 peptide in murine tumor models To demonstrate the therapeutic potential of vaccination using the Arglong2 peptide, mouse models were developed. Because the corresponding Arglong2 sequence in mice differs by only two amino acids, the human Arglong2 sequence was used in subsequent experiments. A comparison of the human and mouse Arglong2 sequences is shown below: Human ArgLong2 (SEQ ID NO: 1) ISAKDIVYIGLRDVDPGEHYILKTLGIKYFSMTEVDRL Mouse ArgLong2 (SEQ ID NO: 2) ISAKDIVYIGLRDVDPGEHYIIKTLGIKYFSMTEVDKL MATERIALS AND METHODS Vaccination with peptides from C57BL / 6 mice The animals were vaccinated subcutaneously with 100 µg of peptide in DMSO / H2O in a 1:1 emulsion with incomplete Montanide ISA 51 VG. Montanide ISA 51 VG + DMSO / H2O served as a control vaccine. For subsequent analysis of the immune response to the ArgLong2 peptide, mice were sacrificed on day 7, and the spleen and draining lymph nodes (dINs) were collected for ELISPOT setup. ELISPOT peptide-specific response analysis Murine immune cells were subjected to ELISPOT analysis. Loose cell suspension was prepared from spleen or dIN by passing it through a cell filter. After lysis of the red blood cells, 0.6–0.8 x 10⁶ cells / well were seeded into ELISPOT plates coated with anti-IFNγ antibody. The peptide of interest was added to the designated wells, and the cells were incubated overnight with the peptide. The following day, the cells were removed, the plates were washed, and the cells were cultured. Lfrfrrnn / Lznz / e / YiAi were incubated with biotinylated detection antibody. Finally, after the addition of streptavidin-ALP and the substrate, visible spots appeared. Each spot corresponded to an individual IFNγ-producing cell. The plates were analyzed on an Immunospot analyzer and plotted. Tumor vaccination of female C57BL / 6 mice, 15-16 / 17-20 weeks of age, 15 animals per group Each animal was inoculated subcutaneously in the right flank with 0.5 x 10⁶ syngeneic tumor cells in 100 μL of medium. Both the B16 F10 melanoma syngeneic cell line and the MC38 colon adenocarcinoma syngeneic cell line were used. Vaccinations began on day 0 and were repeated weekly (day 7 and day 14). Peptide and control vaccinations were performed as previously described. Tumor growth was monitored and tumors were measured approximately every two days. Tumor volume was calculated as V [mm3] = LxW2 / 2 (where L is the longest diameter and W is perpendicular to L). The maximum tumor size before euthanasia of the mice was 864 mm3 (L = 12 mm, W = 12 mm). RESULTS ArgLong2 was found to be highly immunogenic in C57BL / 6 mice, as demonstrated by the high frequency of vaccine-specific T-cell responses detected after a single vaccination (Figure 6). In tumor studies, ArgLong2 vaccines significantly delayed tumor growth compared to control vaccination. This tumor growth delay was observed in both the MC38 model for colon adenocarcinoma (Figure 7) and the B16 model for melanoma (Figure 8). Example 4: ArqLong2-specific T lymphocyte clones recognize arginase-1-expressing THP-1 cells MATERIALS AND METHODS Generation of ArgLong2-specific T lymphocyte clones ArgLong2 clone cultures were generated from an ArgLong2-specific T cell culture following a conventional rapid expansion protocol (REP): ArgLong2-specific cells were separated by magnetic bead sorting from TNFα-producing T cells and used for limited dilution cloning in 96-well plates with ~1 Lbfrrnn / Lznz / e / YiAi cell / well. Each well contained 200 μI of REP mixture (irradiated feeder cells from 3 different leukoplakic layers, aCD3 antibody and 6000 U / ml of IL-2) to promote the growth of ArgLong2-specific T lymphocytes. Quantification of arginase 1 mRNA in THP-1 cells by qPCR: THP-1 cells were stimulated with 20 ng / ml of IL-13 (TriChem) for 48 hours. Cells were harvested, washed in PBS, and pelleted by centrifugation at 300 g for 5 minutes. The pellets were kept on ice and resuspended in 350 µL of RLT Plus buffer (Qiagen). RNA was purified using the RNAeasy kit (Qiagen) according to the manufacturer's instructions, with final elution in 30 µL of RNA-free water. RNA concentration was measured using a NanoDrop 2000 spectrophotometer (Thermo Scientific). RNA was stored at -80 °C. Total RNA was reverse transcribed using the High-Throughput cDNA Reverse Transcription Kit (Applied Biosystems). For each reaction, 1000 ng of RNA was reverse transcribed. For RT-qPCR, the cDNA was diluted 1:5 and analyzed using the TaqMan gene expression assay on a Roche Lightcycler 480 instrument. RT-qPCRs were performed in quadruplicate, and the data were analyzed using the ddCT method with normalization to the expression level of the constitutive gene RPLPOy from the control sample. For low-concentration samples that did not amplify, Ct was set at 40. Controls without reverse transcriptase (cDNA reaction setup without reverse transcriptase) served as specific amplification controls. The human Arg1 primer was acquired from Thermo Fisher (undisclosed sequence, product number Hs00163660_m1). Determination of THP-1 cell recognition by ArgLong2-specific T lymphocytes Untreated and IL-4 / IL-13-treated THP-1 cells were washed and divided into two groups. HLA-DR / DQ / DP blocking antibody (clone TÜ39) was added to the first group at a concentration of 10 pg / ml for 20 min at 37 °C. The second group of THP-1 cells was left untreated. After 20 min of HLA-II blocking, the THP-1 cells were washed. IL-4 / IL-13-treated THP-1 cells (with or without HLA-II blocking) were mixed with ArgLong2 peptide-specific T lymphocytes in a 2:1 effector:target ratio and then processed according to the conventional intracellular cytokine staining protocol. Lirfrrnn / Lznz / e / YiAi RESULTS To further evaluate the functionality of ArgLong2-specific T lymphocytes, T lymphocyte clones were generated from a previously identified healthy donor with a strong response to ArgLong2, and their ability to specifically recognize arginase-expressing targets was examined. Th2 cytokines, such as IL-4 or IL-13, are known to upregulate ARG1 expression in myeloid cells. To test whether ArgLong2-specific T lymphocytes would specifically recognize myeloid cells treated with Th2 cytokines, the ability of ArgLong2 T lymphocyte clones to recognize the HLA-paired THP1 monocytic cell line that was previously stimulated 48 hours prior with IL-4 (100 U / ml) or IL-13 (20 U / ml) was tested. THP-1 treated with Th2 cytokines showed an increase in arginase 1 expression. In this regard, Figure 9C shows that arginase 1 expression is induced in THP-1 cells when they are pretreated with IL-13, thereby increasing the presentation of arginase 1-derived peptide epitopes on the surface of these cells. ArgLong2-specific CD4 T cell clones were shown to recognize IL-4 and IL-13-treated THP-1 cells, as indicated by the increased production of TNFα and IFNγ against these cells compared to untreated THP-1 cells (Figure 9A). Blocking HLA class II molecules abolishes the increased recognition of IL-4 or IL-13-treated THP-1 cells, demonstrating that the enhanced recognition of IL-4 and IL-13-treated THP-1 cells depends on the presentation of ARG1 peptides to HLA class II molecules. Figure 9B illustrates representative data from Figure 9A in dot plot format, showing IFNγ and TNFα production in response to IL-4 and IL-13-treated THP-1 cells with or without HLA class II blockade. In a separate experiment, PBMCs from a healthy donor (HD22, which are known to have a pre-existing ex vivo response against ArgLong2) were treated with IL-4 (100 U / ml) or IL-13 (20 U / ml) for 7 days to increase the presentation of arginase-1-derived peptides in the PBMC culture and thereby stimulate intrinsic ArgLong2-specific T lymphocytes present in the PBMCs. After 7 days of stimulation with IL-4 or IL-13, the PBMCs were analyzed using the IFNγ ELISPOT assay to assess changes in the frequency of ArgLong2-specific T lymphocytes. Increased responses to ArgLong2 were observed in PBMC cultures treated with IL-4 and IL-13 compared to the untreated control. The magnitude of the response to Lbfrrnn / Lznz / e / YiAi IL-13-stimulated ArgLong2 was comparable to the responses observed after stimulation with ArgLong2 peptide in vitro, suggesting strong activation of arginase 1-specific cells under Th2 cytokine conditions. SEQUENCES SEQ ID NO Sequence Name Starting Position Ending Position 1 ISAKDIVYIGLRDVDPGEHYILKTLGIKYFSMTEVDRL ArgLong2 169 206 2 ISAKDIVYIGLRDVDPGEHYIIKTLGIKYFSMTEVDKL* mArg Long2 169 206 3 ISAKDIVYIGLRDVDPGEHYILKTLGIKYFSM ArgLong3 169 200 4 ISAKDIVYIGLRDVDPGEHYIIKTLGIKYFSM* mArgLong3 169 200 5 ISAKDIVYIGLRDVDPGEHYILKTLGIKYFSMTEVDRLGIGK ArgLong 169 210 6 ISAKDIVYIGLRDVDPGEHYIIKTLGIKYFSMTEVDKLGIGK* mArg Long 169 210 7 AKDIVYIGLRDVDPGEHYIL Arg1-18 171 190 8 DVDPGEHYILKTLGIKYFSM Arg1-19 181 200 9 KTLGIKYFSMTEVDRLGIGK Arg1-20 191 210 * indicates a murine arginase 1 sequence that includes at least one difference from the corresponding region of human arginase 1. Remains that are not identical to the corresponding human sequence are in bold and underlined. Murine and human arginase 1 are the same length, so the start and end positions are the same. Full-length human arginase 1 (NP_000036.2) (SEQ ID NO: 10) MSAKSRTIGI IGAPFSKGQP RGGVEEGPTV LRKAGLLEKL KEQECDVKDY GDLPFADIPN DSPFQIVKNP RSVGKASEQL AGKVAEVKKN GRISLVLGGD HSLAIGSISG HARVHPDLGV IWVDAHTDIN TPLTTTSGNL HGQPVSFLLK ELKGKIPDVP GFSWVTPCIS AKDIVYIGLR 15 DVDPGEHYIL KTLGIKYFSM TEVDRLGIGK VMEETLSYLL GRKKRPIHLS FDVDGLDPSF TPATGTPVVG GLTYREGLYI TEEIYKTGLL SGLDIMEVNP SLGKTPEEVT RTVNTAVAIT LACFGLAREG NHKPIDYLNP PK The region identified as a hotspot for immunogenicity is shown in bold and underlined. Full-length murine arginase 1 (NP_031508.1) (SEQ ID NO: 11) MSSKPKSLEI IGAPFSKGQP RGGVEKGPAA LRKAGLLEKL KETEYDVRDH GDLAFVDVPN DSSFQIVKNP RSVGKANEEL AGVVAEVQKN GRVSVVLGGD HSLAVGSISG HARVHPDLGV IWVDAHTDIN TPLTSGNTLTSPVKFKFKFPGVPLL GFSWVTPCIS AKDIVYIGLR DVDPGEHYII KTLGIKYFSM TEVDKLGIGK VMEETFSYLL GRKKRPIHLS FDVDGLDPAF TPATGTPVLG GLSYREGLYI TEEIYKTGLL SGLDIMEVNP TLGKTAEEVK STVNTAVALT LACFGTQREG NHKPGTDYLK PPK The region identified as a hot spot for immunogenicity is shown 5 in bold and underlined Hot spot in human arginase 1 - positions 161-210 of SEQ ID NO: 10 GFSWVTPCISAKDIVYIGLRDVDPGEHYILKTLGIKYFSMTEVDRLGIGK (SEQ ID NO: 12) Hotspot in murine arginase 1 positions 161 210 of SEQ ID NO: 11 GFSWVTPCISAKDIVYIGLRDVDPGEHYIIKTLGIKYKFSMTEVDKLGIGK (SEQ ID NO: 13) Remains that are not identical to the corresponding human sequence are in bold and underlined. Lbfrrnn / Lznz / e / YiAi Lbfrrnn / Lznz / e / YiAi

Claims

1. A polypeptide consisting of any one of the following amino acid sequences: a. ISAKDIVYIGLRDVDPGEHYILKTLGIKYFSMTEVDRL (SEQ ID NO:1); b. ISAKDIVYIGLRDVDPGEHYIIKTLGIKYFSMTEVDKL (SEQ ID NO: 2); c. ISAKDIVYIGLRDVDPGEHYILKTLGIKYFSM (SEQ ID NO:3); d. ISAKDIVYIGLRDVDPGEHYIIKTLGIKYFSM (SEQ ID NO:4); e. ISAKDIVYIGLRDVDPGEHYILKTLGIKYFSMTEVDRLGIGK (SEQ ID NO:5); f. ISAKDIVYIGLRDVDPGEHYIIKTLGIKYFSMTEVDKLGIGK (SEQ ID NO:6); g a sequence according to any one of a. - f. wherein up to three amino acids are replaced by conservative substitution, provided that said polypeptide does not show significantly reduced immunogenicity for arginasal compared to the polypeptide consisting of the corresponding sequence in which no substitution is made; or h. a polynucleotide encoding the polypeptide of any one of a. - g., optionally contained within a vector.

2. The polypeptide of claim 1, consisting of the amino acid sequence of SEQ ID NO:

1.

3. The polypeptide of claim 1 or 2, wherein the carboxy-terminal amino acid is replaced with the corresponding amide.

4. A composition comprising the polypeptide or polynucleotide of any one of claims 1 to 3 and an adjuvant.

5. A composition according to claim 4, comprising at least one pharmaceutically acceptable diluent, carrier or preservative.

6. A composition according to claim 4 or 5, wherein the adjuvant is selected from the group consisting of bacterial DNA-based adjuvants, oil / surfactant-based adjuvants, viral dsRNA-based adjuvants, imidazoquinolines, and a Montanide ISA adjuvant.

7. A method for treating or preventing a disease or condition in a subject, the method comprising administering to the subject the polypeptide or polynucleotide of any one of claims 1 to 3 or the composition of claims 4 to 6.

8. The method of claim 7, wherein the disease or condition is characterized at least in part by inappropriate or excessive immunosuppressive function of an arginase, and / or wherein said disease or condition is cancer.

9. The method of claim 7 or 8, wherein the disease or condition is cancer and, optionally, wherein the method further comprises the simultaneous or sequential administration of an additional cancer therapy, preferably an antibody. 5 10. The method of any one of claims 7 to 9, wherein said cancer is breast, lung, colon or prostate cancer, or is a melanoma, or is a leukemia, preferably acute myeloid leukemia (SMA).

11. A method for stimulating arginasal-specific T lymphocytes, the method comprising contacting the cells with the polypeptide of any one of claims 1 to 3 or with the composition of claims 4 to 6.

12. The method of claim 11, wherein the cells are present in a sample taken from a healthy subject or a cancer patient, optionally a tumor sample.