Abstract
The fundamental job of the immune system is to discriminate self from nonself. To achieve this, the immune system is actively tolerized against self proteins. When pathogens enter a host, they introduce foreign proteins to which the host is not tolerant, and an immune response ensues. In contrast, tumors represent a special case, as the vast majority of tumor proteins are “self” and hence do not trigger immune activation. However, mutation of genes important for regulation of cell growth is the underlying cause of cancer and any point mutation, insertion, reading frame-shift or protein fusion that generates a new protein sequence could theoretically be recognized as foreign by the immune system. With the advent of high-throughput sequencing technologies, we have entered an era where the tumor and germline genomes of individual patients can be sequenced, such that the entire repertoire of tumor-specific mutations can be known. To date, more than 78,000 somatic mutations have been reported in human cancer. While the prospect of targeting this huge diversity of mutations via pharmacological approaches appears daunting, T-cell-based treatments may offer a practical alternative owing to the enormous repertoire of antigen receptors expressed by the human T-cell compartment. To what extent are cancer mutations recognized by the immune system? To what extent can they be targeted by immunotherapy? Here, we review the work to date on these questions with a focus on tumor-specific mutations that have transitioned from basic laboratory investigations through to clinical trials in humans. Our goal is to identify the major issues that need to be resolved to enable advances in DNA sequencing to be translated to effective T-cell therapies in the clinic.
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References
Bardelli A, Parsons DW et al (2003). Mutational analysis of the tyrosine kinome in colorectal cancers. Science 300:949.
Greenman C, Stephens P et al (2007). Patterns of somatic mutation in human cancer genomes. Nature 446:153–158.
Ding L, Getz G et al (2008). Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455:1069–1075.
Wood LD, Parsons DW et al (2007). The genomic landscapes of human breast and colorectal cancers. Science 318:1108–1113.
Shah SP, Morin RD et al (2009). Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature 461:809–813.
Jones S, Zhang X et al (2008). Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321:1801–1806.
Parsons DW, Jones S et al (2008). An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812.
Loeb LA, Bielas JH et al (2008). Cancers exhibit a mutator phenotype: clinical implications. Cancer Res 68:3551–3557; discussion 3557.
Lengauer C, Kinzler KW et al (1998). Genetic instabilities in human cancers. Nature 396:643–649.
Buckowitz A, Knaebel HP et al (2005). Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases. Br J Cancer 92:1746–1753.
Lakhani SR (1999). The pathology of familial breast cancer: morphological aspects. Breast Cancer Res 1:31–35.
Kuroda H, Tamaru J et al (2005). Immunophenotype of lymphocytic infiltration in medullary carcinoma of the breast. Virchows Arch 446:10–14.
Clarke B, Tinker AV et al (2009). Intraepithelial T cells and prognosis in ovarian carcinoma: novel associations with stage, tumor type, and BRCA1 loss. Mod Pathol 22:393–402.
Forbes SA, Bhamra G et al (2008). The Catalogue of Somatic Mutations in Cancer (COSMIC). Curr Protoc Hum Genet Chapter 10: Unit 10 11.
Schinzel AC, and Hahn WC (2008). Oncogenic transformation and experimental models of human cancer. Front Biosci 13:71–84.
Beerenwinkel N, Antal T et al (2007). Genetic progression and the waiting time to cancer. PLoS Comput Biol 3:e225.
Stratton MR, Campbell PJ et al (2009). The cancer genome. Nature 458:719–724.
Vyas JM, Van der Veen AG et al (2008). The known unknowns of antigen processing and presentation. Nat Rev Immunol 8:607–618.
Rangel LB, Agarwal R et al (2004). Anomalous expression of the HLA-DR alpha and beta chains in ovarian and other cancers. Cancer Biol Ther 3:1021–1027.
Liu T, Liu W et al (2009). Computational prediction of the specificities of proteasome interaction with antigen protein. Cell Mol Immunol 6:135–142.
Horton R, Wilming L et al (2004). Gene map of the extended human MHC. Nat Rev Genet 5:889–899.
Bevan MJ (2006). Cross-priming. Nat Immunol 7:363–365.
Arstila TP, Casrouge A et al (1999). A direct estimate of the human alphabeta T cell receptor diversity. Science 286:958–961.
Echchakir H, Mami-Chouaib F et al (2001). A point mutation in the alpha-actinin-4 gene generates an antigenic peptide recognized by autologous cytolytic T lymphocytes on a human lung carcinoma. Cancer Res 61:4078–4083.
Sensi M, and Anichini A (2006). Unique tumor antigens: evidence for immune control of genome integrity and immunogenic targets for T cell-mediated patient-specific immunotherapy. Clin Cancer Res 12:5023–5032.
Jia J, Cui J et al (2009). Genome-scale search of tumor-specific antigens by collective analysis of mutations, expressions and T-cell recognition. Mol Immunol 46:1824–1829.
Wang HY, Zhou J et al (2002). Identification of a mutated fibronectin as a tumor antigen recognized by CD4+ T cells: its role in extracellular matrix formation and tumor metastasis. J Exp Med 195:1397–1406.
Gaudin C, Kremer F et al (1999). A hsp70-2 mutation recognized by CTL on a human renal cell carcinoma. J Immunol 162:1730–1738.
Pieper R, Christian RE et al (1999). Biochemical identification of a mutated human melanoma antigen recognized by CD4(+) T cells. J Exp Med 189:757–766.
Baurain JF, Colau D et al (2000). High frequency of autologous anti-melanoma CTL directed against an antigen generated by a point mutation in a new helicase gene. J Immunol 164:6057–6066.
Huang J, El-Gamil M et al (2004). T cells associated with tumor regression recognize frameshifted products of the CDKN2A tumor suppressor gene locus and a mutated HLA class I gene product. J Immunol 172:6057–6064.
Linard B, Bezieau S et al (2002). A RAS-mutated peptide targeted by CTL infiltrating a human melanoma lesion. J Immunol 168:4802–4808.
Robbins PF, El-Gamil M et al (1996). A mutated beta-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes. J Exp Med 183:1185–1192.
Novellino L, Renkvist N et al (2003). Identification of a mutated receptor-like protein tyrosine phosphatase kappa as a novel, class II HLA-restricted melanoma antigen. J Immunol 170:6363–6370.
Kawakami Y, Wang X et al (2001). Isolation of a new melanoma antigen, MART-2, containing a mutated epitope recognized by autologous tumor-infiltrating T lymphocytes. J Immunol 166:2871–2877.
Karanikas V, Colau D et al (2001). High frequency of cytolytic T lymphocytes directed against a tumor-specific mutated antigen detectable with HLA tetramers in the blood of a lung carcinoma patient with long survival. Cancer Res 61:3718–3724.
Mami-Chouaib F, Echchakir H et al (2002). Antitumor cytotoxic T-lymphocyte response in human lung carcinoma: identification of a tumor-associated antigen. Immunol Rev 188:114–121.
Zorn E, and Hercend T (1999). A natural cytotoxic T cell response in a spontaneously regressing human melanoma targets a neoantigen resulting from a somatic point mutation. Eur J Immunol 29:592–601.
Wang HY, Peng G et al (2005). Recognition of a new ARTC1 peptide ligand uniquely expressed in tumor cells by antigen-specific CD4+ regulatory T cells. J Immunol 174:2661–2670.
Coulie PG, Lehmann F et al (1995). A mutated intron sequence codes for an antigenic peptide recognized by cytolytic T lymphocytes on a human melanoma. Proc Natl Acad Sci USA 92:7976–7980.
Topalian SL, Gonzales MI et al (2002). Revelation of a cryptic major histocompatibility complex class II-restricted tumor epitope in a novel RNA-processing enzyme. Cancer Res 62:5505–5509.
Maccalli C, Li YF et al (2003). Identification of a colorectal tumor-associated antigen (COA-1) recognized by CD4(+) T lymphocytes. Cancer Res 63:6735–6743.
Van Elsas A, Nijman HW et al (1995). Induction and characterization of cytotoxic T-lymphocytes recognizing a mutated p21RAS peptide presented by HLA-A*0201. Int J Cancer 61:389–396.
Qin H, Chen W et al (1995). CD4+ T-cell immunity to mutated RAS protein in pancreatic and colon cancer patients. Cancer Res 55:2984–2987.
Abrams SI, Hand PH et al (1996). Mutant RAS epitopes as targets for cancer vaccines. Semin Oncol 23:118–134.
Sharkey MS, Lizee G et al (2004). CD4(+) T-cell recognition of mutated B-RAF in melanoma patients harboring the V599E mutation. Cancer Res 64:1595–1599.
Schwitalle Y, Linnebacher M et al (2004). Immunogenic peptides generated by frameshift mutations in DNA mismatch repair-deficient cancer cells. Cancer Immun 4:14.
Ripberger E, Linnebacher M et al (2003). Identification of an HLA-A0201-restricted CTL epitope generated by a tumor-specific frameshift mutation in a coding microsatellite of the OGT gene. J Clin Immunol 23:415–423.
Linnebacher M, Gebert J et al (2001). Frameshift peptide-derived T-cell epitopes: a source of novel tumor-specific antigens. Int J Cancer 93:6–11.
Worley BS, van den Broeke LT et al (2001). Antigenicity of fusion proteins from sarcoma-associated chromosomal translocations. Cancer Res 61:6868–6875.
Yotnda P, Garcia F et al (1998). Cytotoxic T cell response against the chimeric ETV6-AML1 protein in childhood acute lymphoblastic leukemia. J Clin Invest 102:455–462.
Yotnda P, Firat H et al (1998). Cytotoxic T cell response against the chimeric p210 BCR-ABL protein in patients with chronic myelogenous leukemia. J Clin Invest 101:2290–2296.
Nieda M, Nicol A et al (1998). Dendritic cells stimulate the expansion of bcr-abl specific CD8+ T cells with cytotoxic activity against leukemic cells from patients with chronic myeloid leukemia. Blood 91:977–983.
Bosch GJ, Joosten AM et al (1996). Recognition of BCR-ABL positive leukemic blasts by human CD4+ T cells elicited by primary in vitro immunization with a BCR-ABL breakpoint peptide. Blood 88:3522–3527.
Reddy EP, Reynolds RK et al (1982). A point mutation is responsible for the acquisition of transforming properties by the T24 human bladder carcinoma oncogene. Nature 300:149–152.
Tabin CJ, Bradley SM et al (1982). Mechanism of activation of a human oncogene. Nature 300:143–149.
Fossum B, Olsen AC et al (1995). CD8+ T cells from a patient with colon carcinoma, specific for a mutant p21-RAS-derived peptide (Gly13-- > Asp), are cytotoxic towards a carcinoma cell line harbouring the same mutation. Cancer Immunol Immunother 40:165–172.
Gjertsen MK, Bjorheim J et al (1997). Cytotoxic CD4+ and CD8+ T lymphocytes, generated by mutant p21-RAS (12Val) peptide vaccination of a patient, recognize 12Val-dependent nested epitopes present within the vaccine peptide and kill autologous tumour cells carrying this mutation. Int J Cancer 72:784–790.
Juretic A, Jurgens-Gobel J et al (1996). Cytotoxic T-lymphocyte responses against mutated p21 RAS peptides: an analysis of specific T-cell-receptor gene usage. Int J Cancer 68:471–478.
Gjertsen MK, Bakka A et al (1995). Vaccination with mutant RAS peptides and induction of T-cell responsiveness in pancreatic carcinoma patients carrying the corresponding RAS mutation. Lancet 346:1399–1400.
Gjertsen MK, Buanes T et al (2001). Intradermal RAS peptide vaccination with granulocyte-macrophage colony-stimulating factor as adjuvant: clinical and immunological responses in patients with pancreatic adenocarcinoma. Int J Cancer 92:441–450.
Khleif SN, Abrams SI et al (1999). A phase I vaccine trial with peptides reflecting RAS oncogene mutations of solid tumors. J Immunother 22:155–165.
Abrams SI, Khleif SN et al (1997). Generation of stable CD4+ and CD8+ T cell lines from patients immunized with RAS oncogene-derived peptides reflecting codon 12 mutations. Cell Immunol 182:137–151.
Toubaji A, Achtar M et al (2008). Pilot study of mutant RAS peptide-based vaccine as an adjuvant treatment in pancreatic and colorectal cancers. Cancer Immunol Immunother 57:1413–1420.
Meyer RG, Korn S et al (2007). An open-label, prospective phase I/II study evaluating the immunogenicity and safety of a RAS peptide vaccine plus GM-CSF in patients with non-small cell lung cancer. Lung Cancer 58:88–94.
Carbone DP, Ciernik IF et al (2005). Immunization with mutant p53- and K-RAS-derived peptides in cancer patients: immune response and clinical outcome. J Clin Oncol 23:5099–5107.
Hunger RE, Brand CU et al (2001). Successful induction of immune responses against mutant RAS in melanoma patients using intradermal injection of peptides and GM-CSF as adjuvant. Exp Dermatol 10:161–167.
Shtivelman E, Lifshitz B et al (1986). Alternative splicing of RNAs transcribed from the human ABL gene and from the BCR-ABL fused gene. Cell 47:277–284.
Bocchia M, Wentworth PA et al (1995). Specific binding of leukemia oncogene fusion protein peptides to HLA class I molecules. Blood 85:2680–2684.
Bocchia M, Korontsvit T et al (1996). Specific human cellular immunity to BCR-ABL oncogene-derived peptides. Blood 87:3587–3592.
Greco G, Fruci D et al (1996). Two BRC-ABL junction peptides bind HLA-A3 molecules and allow specific induction of human cytotoxic T lymphocytes. Leukemia 10:693–699.
Buzyn A, Ostankovitch M et al (1997). Peptides derived from the whole sequence of BCR-ABL bind to several class I molecules allowing specific induction of human cytotoxic T lymphocytes. Eur J Immunol 27:2066–2072.
Clark RE, Dodi IA et al (2001). Direct evidence that leukemic cells present HLA-associated immunogenic peptides derived from the BCR-ABL b3a2 fusion protein. Blood 98:2887–2893.
ten Bosch GJ, Toornvliet AC et al (1995). Recognition of peptides corresponding to the joining region of p210BCR-ABL protein by human T cells. Leukemia 9:1344–1348.
Pawelec G, Max H et al (1996). BCR/ABL leukemia oncogene fusion peptides selectively bind to certain HLA-DR alleles and can be recognized by T cells found at low frequency in the repertoire of normal donors. Blood 88:2118–2124.
Mannering SI, McKenzie JL et al (1997). HLA-DR1-restricted bcr-abl (b3a2)-specific CD4+ T lymphocytes respond to dendritic cells pulsed with b3a2 peptide and antigen-presenting cells exposed to b3a2 containing cell lysates. Blood 90:290–297.
Pinilla-Ibarz J, Cathcart K et al (2000). Vaccination of patients with chronic myelogenous leukemia with BCR-ABL oncogene breakpoint fusion peptides generates specific immune responses. Blood 95:1781–1787.
Cathcart K, Pinilla-Ibarz J et al (2004). A multivalent BCR-ABL fusion peptide vaccination trial in patients with chronic myeloid leukemia. Blood 103:1037–1042.
Bocchia M, Gentili S et al (2005). Effect of a p210 multipeptide vaccine associated with imatinib or interferon in patients with chronic myeloid leukaemia and persistent residual disease: a multicentre observational trial. Lancet 365:657–662.
Rojas JM, Knight K et al (2007). Clinical evaluation of BCR-ABL peptide immunisation in chronic myeloid leukaemia: results of the EPIC study. Leukemia 21:2287–2295.
Maslak PG, Dao T et al (2008). A pilot vaccination trial of synthetic analog peptides derived from the BCR-ABL breakpoints in CML patients with minimal disease. Leukemia 22:1613–1616.
Jain N, Reuben JM et al (2009). Synthetic tumor-specific breakpoint peptide vaccine in patients with chronic myeloid leukemia and minimal residual disease: a phase 2 trial. Cancer 115:3924–3934.
Parker KC, Bednarek MA et al (1994). Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. J Immunol 152:163–175.
Rammensee H, Bachmann J et al (1999). SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics 50:213–219.
Larsen MV, Lundegaard C et al (2007). Large-scale validation of methods for cytotoxic T-lymphocyte epitope prediction. BMC Bioinformatics 8:424.
Larsen MV, Lundegaard C et al (2005). An integrative approach to CTL epitope prediction: a combined algorithm integrating MHC class I binding, TAP transport efficiency, and proteasomal cleavage predictions. Eur J Immunol 35:2295–2303.
Lundegaard C, Lamberth K et al (2008). NetMHC-3.0: accurate web accessible predictions of human, mouse and monkey MHC class I affinities for peptides of length 8–11. Nucleic Acids Res 36:W509–512.
Doytchinova IA, Guan P et al (2006). EpiJen: a server for multistep T cell epitope prediction. BMC Bioinformatics 7:131.
Hakenberg J, Nussbaum AK et al (2003). MAPPP: MHC class I antigenic peptide processing prediction. Appl Bioinformatics 2:155–158.
Zhang Q, Wang P et al (2008). Immune epitope database analysis resource (IEDB-AR). Nucleic Acids Res 36:W513–518.
Westrop SJ, Grageda N et al (2009). Novel approach to recognition of predicted HIV-1 Gag B3501-restricted CD8 T-cell epitopes by HLA-B3501(+) patients: confirmation by quantitative ELISpot analyses and characterisation using multimers. J Immunol Meth 341:76–85.
Wulf M, Hoehn P et al (2009). Identification of human MHC class I binding peptides using the iTOPIA- epitope discovery system. Meth Mol Biol 524:361–367.
Wilson CC, Olson WC et al (1999). HIV-1-specific CTL responses primed in vitro by blood-derived dendritic cells and Th1-biasing cytokines. J Immunol 162:3070–3078.
Tuting T, Wilson CC et al (1998). Autologous human monocyte-derived dendritic cells genetically modified to express melanoma antigens elicit primary cytotoxic T cell responses in vitro: enhancement by cotransfection of genes encoding the Th1-biasing cytokines IL-12 and IFN-alpha. J Immunol 160:1139–1147.
Pascolo S (2005). HLA class I transgenic mice: development, utilisation and improvement. Expert Opin Biol Ther 5:919–938.
Hunter C, Smith R et al (2006). A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Res 66:3987–3991.
The Cancer Genome Atlas (2008). Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068.
O’Hare T, Eide CA et al (2008). New BCR-ABL inhibitors in chronic myeloid leukemia: keeping resistance in check. Expert Opin Investig Drugs 17:865–878.
Yamamoto H, Toyooka S et al (2009). Impact of EGFR mutation analysis in non-small cell lung cancer. Lung Cancer 63:315–321.
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Nelson, B.H., Webb, J.R. (2011). Tumor-Specific Mutations as Targets for Cancer Immunotherapy. In: Medin, J., Fowler, D. (eds) Experimental and Applied Immunotherapy. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-980-2_7
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