Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The landscape of T cell antigens for cancer immunotherapy

Nature Cancer volume 4, pages 937–954 (2023)Cite this article

Subjects

Abstract

The remarkable capacity of immunotherapies to induce durable regression in some patients with metastatic cancer relies heavily on T cell recognition of tumor-presented antigens. As checkpoint-blockade therapy has limited efficacy, tumor antigens have the potential to be exploited for complementary treatments, many of which are already in clinical trials. The surge of interest in this topic has led to the expansion of the tumor antigen landscape with the emergence of new antigen categories. Nonetheless, how different antigens compare in their ability to elicit efficient and safe clinical responses remains largely unknown. Here, we review known cancer peptide antigens, their attributes and the relevant clinical data and discuss future directions.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: T cell antigens at the center of all immunotherapy modalities.
Fig. 2: Advances and discoveries in tumor antigen research.
Fig. 3: Methods for the identification of cancer T cell antigens.
Fig. 4: Tumor antigens recognized by T cells.

Similar content being viewed by others

References

  1. Leko, V. & Rosenberg, S. A. Identifying and targeting human tumor antigens for T cell-based immunotherapy of solid tumors. Cancer Cell 38, 454–472 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Waldman, A. D., Fritz, J. M. & Lenardo, M. J. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat. Rev. Immunol. 20, 651–668 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Lythe, G., Callard, R. E., Hoare, R. L. & Molina-Paris, C. How many TCR clonotypes does a body maintain. J. Theor. Biol. 389, 214–224 (2016).

    PubMed  PubMed Central  Google Scholar 

  4. Wosen, J. E., Mukhopadhyay, D., Macaubas, C. & Mellins, E. D. Epithelial MHC class II expression and its role in antigen presentation in the gastrointestinal and respiratory tracts. Front. Immunol. 9, 2144 (2018).

    PubMed  PubMed Central  Google Scholar 

  5. Spranger, S., Dai, D., Horton, B. & Gajewski, T. F. Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell 31, 711–723 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Salmon, H. et al. Expansion and activation of CD103+ dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immunity 44, 924–938 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Coulie, P. G., Van den Eynde, B. J., van der Bruggen, P. & Boon, T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat. Rev. Cancer 14, 135–146 (2014).

    CAS  PubMed  Google Scholar 

  8. Tran, E. et al. T-cell transfer therapy targeting mutant KRAS in cancer. N. Engl. J. Med. 375, 2255–2262 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Tran, E. et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344, 641–645 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Garcia-Garijo, A., Fajardo, C. A. & Gros, A. Determinants for neoantigen identification. Front. Immunol. 10, 1392 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Schumacher, T. N., Scheper, W. & Kvistborg, P. Cancer neoantigens. Annu. Rev. Immunol. 37, 173–200 (2019).

    CAS  PubMed  Google Scholar 

  12. Bartok, O. et al. Anti-tumour immunity induces aberrant peptide presentation in melanoma. Nature 590, 332–337 (2021).

    CAS  PubMed  Google Scholar 

  13. Kalaora, S. et al. Identification of bacteria-derived HLA-bound peptides in melanoma. Nature 592, 138–143 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Ouspenskaia, T. et al. Unannotated proteins expand the MHC-I-restricted immunopeptidome in cancer. Nat. Biotechnol. 40, 209–217 (2022).

    CAS  PubMed  Google Scholar 

  15. Pearlman, A. H. et al. Targeting public neoantigens for cancer immunotherapy. Nat. Cancer 2, 487–497 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Bakker, A. B. et al. Identification of a novel peptide derived from the melanocyte-specific gp100 antigen as the dominant epitope recognized by an HLA-A2.1-restricted anti-melanoma CTL line. Int. J. Cancer 62, 97–102 (1995).

    CAS  PubMed  Google Scholar 

  17. Brichard, V. et al. The tyrosinase gene codes for an antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J. Exp. Med. 178, 489–495 (1993).

    CAS  PubMed  Google Scholar 

  18. Kawakami, Y. et al. Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2-restricted tumor infiltrating lymphocytes. J. Exp. Med. 180, 347–352 (1994).

    CAS  PubMed  Google Scholar 

  19. Nathan, P. et al. Overall survival benefit with tebentafusp in metastatic uveal melanoma. N. Engl. J. Med. 385, 1196–1206 (2021).

    CAS  PubMed  Google Scholar 

  20. Hofmann, O. et al. Genome-wide analysis of cancer/testis gene expression. Proc. Natl Acad. Sci. USA 105, 20422–20427 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. De Plaen, E. et al. Structure, chromosomal localization, and expression of 12 genes of the MAGE family. Immunogenetics 40, 360–369 (1994).

    CAS  PubMed  Google Scholar 

  22. Lurquin, C. et al. Two members of the human MAGEB gene family located in Xp21.3 are expressed in tumors of various histological origins. Genomics 46, 397–408 (1997).

    CAS  PubMed  Google Scholar 

  23. van der Bruggen, P. et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254, 1643–1647 (1991).

    PubMed  Google Scholar 

  24. Huijbers, I. J. et al. Minimal tolerance to a tumor antigen encoded by a cancer-germline gene. J. Immunol. 188, 111–121 (2012).

    CAS  PubMed  Google Scholar 

  25. Woloszynska-Read, A., Mhawech-Fauceglia, P., Yu, J., Odunsi, K. & Karpf, A. R. Intertumor and intratumor NY-ESO-1 expression heterogeneity is associated with promoter-specific and global DNA methylation status in ovarian cancer. Clin. Cancer Res. 14, 3283–3290 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Peri, A. et al. Combined presentation and immunogenicity analysis reveals a recurrent RAS.Q61K neoantigen in melanoma. J. Clin. Invest. https://doi.org/10.1172/JCI129466 (2021).

  28. Duan, F. et al. Genomic and bioinformatic profiling of mutational neoepitopes reveals new rules to predict anticancer immunogenicity. J. Exp. Med. 211, 2231–2248 (2014).

    PubMed  PubMed Central  Google Scholar 

  29. Spierings, E. et al. The minor histocompatibility antigen HA-3 arises from differential proteasome-mediated cleavage of the lymphoid blast crisis (Lbc) oncoprotein. Blood. 102, 621–629 (2003).

    CAS  PubMed  Google Scholar 

  30. Rizvi, N. A. et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).

    PubMed  PubMed Central  Google Scholar 

  32. Van Allen, E. M. et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350, 207–211 (2015).

    PubMed  PubMed Central  Google Scholar 

  33. Lauss, M. et al. Mutational and putative neoantigen load predict clinical benefit of adoptive T cell therapy in melanoma. Nat. Commun. 8, 1738 (2017).

    PubMed  PubMed Central  Google Scholar 

  34. Overman, M. J. et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 18, 1182–1191 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Yarchoan, M., Hopkins, A. & Jaffee, E. M. Tumor mutational burden and response rate to PD-1 inhibition. N. Engl. J. Med. 377, 2500–2501 (2017).

    PubMed  PubMed Central  Google Scholar 

  38. Cercek, A. et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N. Engl. J. Med. 386, 2363–2376 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Merchant, M. et al. Tumor mutational burden and immunotherapy in gliomas. Trends Cancer 7, 1054–1058 (2021).

    CAS  PubMed  Google Scholar 

  40. Segal, N. H. et al. Epitope landscape in breast and colorectal cancer. Cancer Res. 68, 889–892 (2008).

    CAS  PubMed  Google Scholar 

  41. Kalaora, S. & Samuels, Y. in Cancer Immunosurveillance (eds. López-Soto, A. & Folgueras, A. R.) 203–214 (Springer, 2019).

  42. Bassani-Sternberg, M. & Coukos, G. Mass spectrometry-based antigen discovery for cancer immunotherapy. Curr. Opin. Immunol. 41, 9–17 (2016).

    CAS  PubMed  Google Scholar 

  43. Castle, J. C. et al. Exploiting the mutanome for tumor vaccination. Cancer Res. 72, 1081–1091 (2012).

    CAS  PubMed  Google Scholar 

  44. Clark, R. E. et al. Direct evidence that leukemic cells present HLA-associated immunogenic peptides derived from the BCR-ABL b3a2 fusion protein. Blood 98, 2887–2893 (2001).

    CAS  PubMed  Google Scholar 

  45. van der Lee, D. I. et al. Mutated nucleophosmin 1 as immunotherapy target in acute myeloid leukemia. J. Clin. Invest. 129, 774–785 (2019).

    PubMed  PubMed Central  Google Scholar 

  46. McGranahan, N. et al. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution. Sci. Transl. Med. 7, 283ra254 (2015).

    Google Scholar 

  47. Wolfel, T. et al. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 269, 1281–1284 (1995).

    CAS  PubMed  Google Scholar 

  48. Robbins, P. F. et al. A mutated β-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes. J. Exp. Med. 183, 1185–1192 (1996).

    CAS  PubMed  Google Scholar 

  49. Kvistborg, P. et al. TIL therapy broadens the tumor-reactive CD8+ T cell compartment in melanoma patients. Oncoimmunology 1, 409–418 (2012).

    PubMed  PubMed Central  Google Scholar 

  50. Leisegang, M., Kammertoens, T., Uckert, W. & Blankenstein, T. Targeting human melanoma neoantigens by T cell receptor gene therapy. J. Clin. Invest. 126, 854–858 (2016).

    PubMed  PubMed Central  Google Scholar 

  51. Gjertsen, M. K., Saeterdal, I., Saeboe-Larssen, S. & Gaudernack, G. HLA-A3 restricted mutant ras specific cytotoxic T-lymphocytes induced by vaccination with T-helper epitopes. J. Mol. Med. 81, 43–50 (2003).

    CAS  PubMed  Google Scholar 

  52. Gjertsen, M. K., Bjorheim, J., Saeterdal, I., Myklebust, J. & Gaudernack, G. 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 (1997).

    CAS  PubMed  Google Scholar 

  53. Abrams, S. I. et al. 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 (1997).

    CAS  PubMed  Google Scholar 

  54. Ito, D. et al. Immunological characterization of missense mutations occurring within cytotoxic T cell-defined p53 epitopes in HLA-A*0201+ squamous cell carcinomas of the head and neck. Int. J. Cancer 120, 2618–2624 (2007).

    CAS  PubMed  Google Scholar 

  55. Malekzadeh, P. et al. Antigen experienced T cells from peripheral blood recognize p53 neoantigens. Clin. Cancer Res. 26, 1267–1276 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Sharkey, M. S., Lizee, G., Gonzales, M. I., Patel, S. & Topalian, S. L. CD4+ T-cell recognition of mutated B-RAF in melanoma patients harboring the V599E mutation. Cancer Res. 64, 1595–1599 (2004).

    CAS  PubMed  Google Scholar 

  57. Somasundaram, R. et al. Human leukocyte antigen-A2-restricted CTL responses to mutated BRAF peptides in melanoma patients. Cancer Res. 66, 3287–3293 (2006).

    CAS  PubMed  Google Scholar 

  58. Andersen, M. H. et al. Immunogenicity of constitutively active V599EBRaf. Cancer Res. 64, 5456–5460 (2004).

    CAS  PubMed  Google Scholar 

  59. Yamada, T. et al. EGFR T790M mutation as a possible target for immunotherapy; identification of HLA-A*0201-restricted T cell epitopes derived from the EGFR T790M mutation. PLoS ONE 8, e78389 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Chandran, S. S. et al. Immunogenicity and therapeutic targeting of a public neoantigen derived from mutated PIK3CA. Nat. Med. https://doi.org/10.1038/s41591-022-01786-3 (2022).

  61. Kalaora, S. et al. Combined analysis of antigen presentation and T-cell recognition reveals restricted immune responses in melanoma. Cancer Discov. 8, 1366–1375 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Wang, Q. et al. Direct detection and quantification of neoantigens. Cancer Immunol. Res. 7, 1748–1754 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Leidner, R. et al. Neoantigen T-cell receptor gene therapy in pancreatic cancer. N. Engl. J. Med. 386, 2112–2119 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Turajlic, S. et al. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Lancet Oncol. 18, 1009–1021 (2017).

    CAS  PubMed  Google Scholar 

  65. Mansfield, A. S. et al. Neoantigenic potential of complex chromosomal rearrangements in mesothelioma. J. Thorac. Oncol. 14, 276–287 (2019).

    CAS  PubMed  Google Scholar 

  66. Quintas-Cardama, A. & Cortes, J. Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood 113, 1619–1630 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Sasaki, T., Rodig, S. J., Chirieac, L. R. & Janne, P. A. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur. J. Cancer 46, 1773–1780 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Wei, Z. et al. The landscape of tumor fusion neoantigens: a pan-cancer analysis. iScience 21, 249–260 (2019).

    PubMed  PubMed Central  Google Scholar 

  69. Yang, W. et al. Immunogenic neoantigens derived from gene fusions stimulate T cell responses. Nat. Med. 25, 767–775 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Chaisson, M. J. P. et al. Multi-platform discovery of haplotype-resolved structural variation in human genomes. Nat. Commun. 10, 1784 (2019).

    PubMed  PubMed Central  Google Scholar 

  71. Sethi, R. et al. Integrative analysis of structural variations using short-reads and linked-reads yields highly specific and sensitive predictions. PLoS Comput. Biol. 16, e1008397 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Hu, X. et al. TumorFusions: an integrative resource for cancer-associated transcript fusions. Nucleic Acids Res. 46, D1144–D1149 (2018).

    CAS  PubMed  Google Scholar 

  73. Jurtz, V. et al. NetMHCpan-4.0: improved peptide-MHC class I interaction predictions integrating eluted ligand and peptide binding affinity data. J. Immunol. 199, 3360–3368 (2017).

    CAS  PubMed  Google Scholar 

  74. Wang, S., Mao, C. & Liu, S. Peptides encoded by noncoding genes: challenges and perspectives. Signal Transduct. Target Ther. 4, 57 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Guilloux, Y. et al. A peptide recognized by human cytolytic T lymphocytes on HLA-A2 melanomas is encoded by an intron sequence of the N-acetylglucosaminyltransferase V gene. J. Exp. Med. 183, 1173–1183 (1996).

    CAS  PubMed  Google Scholar 

  76. Lupetti, R. et al. Translation of a retained intron in tyrosinase-related protein (TRP) 2 mRNA generates a new cytotoxic T lymphocyte (CTL)-defined and shared human melanoma antigen not expressed in normal cells of the melanocytic lineage. J. Exp. Med. 188, 1005–1016 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Chong, C. et al. Integrated proteogenomic deep sequencing and analytics accurately identify non-canonical peptides in tumor immunopeptidomes. Nat. Commun. 11, 1293 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Robbins, P. F. et al. The intronic region of an incompletely spliced gp100 gene transcript encodes an epitope recognized by melanoma-reactive tumor-infiltrating lymphocytes. J. Immunol. 159, 303–308 (1997).

    CAS  PubMed  Google Scholar 

  79. Uenaka, A. et al. Identification of a unique antigen peptide pRL1 on BALB/c RL male 1 leukemia recognized by cytotoxic T lymphocytes and its relation to the Akt oncogene. J. Exp. Med. 180, 1599–1607 (1994).

    CAS  PubMed  Google Scholar 

  80. Wang, R. F. et al. A breast and melanoma-shared tumor antigen: T cell responses to antigenic peptides translated from different open reading frames. J. Immunol. 161, 3598–3606 (1998).

    CAS  PubMed  Google Scholar 

  81. Graddis, T. J. et al. Tumor immunotherapy with alternative reading frame peptide antigens. Immunobiology 209, 535–544 (2004).

    PubMed  Google Scholar 

  82. Weinzierl, A. O. et al. A cryptic vascular endothelial growth factor T-cell epitope: identification and characterization by mass spectrometry and T-cell assays. Cancer Res. 68, 2447–2454 (2008).

    CAS  PubMed  Google Scholar 

  83. Ronsin, C. et al. A non-AUG-defined alternative open reading frame of the intestinal carboxyl esterase mRNA generates an epitope recognized by renal cell carcinoma-reactive tumor-infiltrating lymphocytes in situ. J. Immunol. 163, 483–490 (1999).

    CAS  PubMed  Google Scholar 

  84. Ho, O. & Green, W. R. Alternative translational products and cryptic T cell epitopes: expecting the unexpected. J. Immunol. 177, 8283–8289 (2006).

    CAS  PubMed  Google Scholar 

  85. Lee, J. Y. et al. Promiscuous methionyl-tRNA synthetase mediates adaptive mistranslation to protect cells against oxidative stress. J. Cell Sci. 127, 4234–4245 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Netzer, N. et al. Innate immune and chemically triggered oxidative stress modifies translational fidelity. Nature 462, 522–526 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Santos, M. et al. Codon misreading tRNAs promote tumor growth in mice. RNA Biol. 15, 773–786 (2018).

    PubMed  PubMed Central  Google Scholar 

  88. Chen, L., Liu, S. & Tao, Y. Regulating tumor suppressor genes: post-translational modifications. Signal Transduct. Target Ther. 5, 90 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Kacen, A. et al. Post-translational modifications reshape the antigenic landscape of the MHC I immunopeptidome in tumors. Nat. Biotechnol. 41, 239–251 (2023).

    CAS  PubMed  Google Scholar 

  90. zur Hausen, H. Viruses in human cancers. Science 254, 1167–1173 (1991).

    CAS  PubMed  Google Scholar 

  91. Wroblewski, L. E., Peek, R. M. Jr. & Wilson, K. T. Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin. Microbiol. Rev. 23, 713–739 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Lin, L. et al. The burden and trends of primary liver cancer caused by specific etiologies from 1990 to 2017 at the global, regional, national, age, and sex level results from the Global Burden of Disease study 2017. Liver Cancer 9, 563–582 (2020).

    PubMed  PubMed Central  Google Scholar 

  93. Bhatt, K. H. et al. Profiling HPV-16-specific T cell responses reveals broad antigen reactivities in oropharyngeal cancer patients. J. Exp. Med. https://doi.org/10.1084/jem.20200389 (2020).

  94. Chabeda, A. et al. Therapeutic vaccines for high-risk HPV-associated diseases. Papillomavirus Res. 5, 46–58 (2018).

    PubMed  Google Scholar 

  95. Quiding-Jarbrink, M., Lundin, B. S., Lonroth, H. & Svennerholm, A. M. CD4+ and CD8+ T cell responses in Helicobacter pylori-infected individuals. Clin. Exp. Immunol. 123, 81–87 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. van Zyl, D. G., Mautner, J. & Delecluse, H. J. Progress in EBV vaccines. Front. Oncol. 9, 104 (2019).

    PubMed  PubMed Central  Google Scholar 

  97. Fluckiger, A. et al. Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage. Science 369, 936–942 (2020).

    CAS  PubMed  Google Scholar 

  98. Ficial, M. et al. Expression of T-cell exhaustion molecules and human endogenous retroviruses as predictive biomarkers for response to nivolumab in metastatic clear cell renal cell carcinoma. Clin. Cancer Res. 27, 1371–1380 (2021).

    CAS  PubMed  Google Scholar 

  99. Jin, B. Y. et al. Engineered T cells targeting E7 mediate regression of human papillomavirus cancers in a murine model. JCI Insight https://doi.org/10.1172/jci.insight.99488 (2018).

  100. Draper, L. M. et al. Targeting of HPV-16+ epithelial cancer cells by TCR gene engineered T Cells directed against E6. Clin. Cancer Res. 21, 4431–4439 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Narunsky-Haziza, L. et al. Pan-cancer analyses reveal cancer-type-specific fungal ecologies and bacteriome interactions. Cell 185, 3789–3806 e3717 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Caballero, O. L. & Chen, Y. T. Cancer/testis (CT) antigens: potential targets for immunotherapy. Cancer Sci. 100, 2014–2021 (2009).

    CAS  PubMed  Google Scholar 

  103. Nejman, D. et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science 368, 973–980 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Johnson, L. A. et al. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 114, 535–546 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. van den Berg, J. H. et al. Case report of a fatal serious adverse event upon administration of T cells transduced with a MART-1-specific T-cell receptor. Mol. Ther. 23, 1541–1550 (2015).

    PubMed  PubMed Central  Google Scholar 

  106. Linette, G. P. et al. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood 122, 863–871 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Morgan, R. A. et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126–129 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Nowicki, T. S. et al. A pilot trial of the combination of transgenic NY-ESO-1-reactive adoptive cellular therapy with dendritic cell vaccination with or without ipilimumab. Clin. Cancer Res. 25, 2096–2108 (2019).

    CAS  PubMed  Google Scholar 

  109. D’Angelo, S. P. et al. Antitumor activity associated with prolonged persistence of adoptively transferred NY-ESO-1 (c259)T cells in synovial sarcoma. Cancer Discov. 8, 944–957 (2018).

    PubMed  PubMed Central  Google Scholar 

  110. Morgan, R. A. et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J. Immunother. 36, 133–151 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Fritsch, E. F. et al. HLA-binding properties of tumor neoepitopes in humans. Cancer Immunol. Res. 2, 522–529 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Sim, M. J. W. et al. High-affinity oligoclonal TCRs define effective adoptive T cell therapy targeting mutant KRAS-G12D. Proc. Natl Acad. Sci. USA 117, 12826–12835 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Martincorena, I. et al. Somatic mutant clones colonize the human esophagus with age. Science 362, 911–917 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Martincorena, I. et al. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Cuevas, M. V. R. et al. Most non-canonical proteins uniquely populate the proteome or immunopeptidome. Cell Rep. 34, 108815 (2021).

    PubMed Central  Google Scholar 

  116. Pataskar, A. et al. Tryptophan depletion results in tryptophan-to-phenylalanine substitutants. Nature 603, 721–727 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Liu, W. et al. Identifying the target cells and mechanisms of merkel cell polyomavirus infection. Cell Host Microbe 19, 775–787 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Tan, A. T. & Schreiber, S. Adoptive T-cell therapy for HBV-associated HCC and HBV infection. Antiviral Res. 176, 104748 (2020).

    CAS  PubMed  Google Scholar 

  119. Nagarsheth, N. B. et al. TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers. Nat. Med. 27, 419–425 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Doran, S. L. et al. T-cell receptor gene therapy for human papillomavirus-associated epithelial cancers: a first-in-human, phase I/II study. J. Clin. Oncol. 37, 2759–2768 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Kwong, D. L. W., Lee, V. H. F. & Nicholls, J. M. in Nasopharyngeal Carcinoma (eds Anne W. M. Lee, Maria Li Lung, & Wai Tong Ng) 337–351 (Academic Press, 2019).

  122. Paulson, K. G. et al. Acquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA. Nat. Commun. 9, 3868 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Yan, F. M. et al. Hepatitis C virus may infect extrahepatic tissues in patients with hepatitis C. World J. Gastroenterol. 6, 805–811 (2000).

    PubMed  PubMed Central  Google Scholar 

  124. McMahan, R. H. & Slansky, J. E. Mobilizing the low-avidity T cell repertoire to kill tumors. Semin. Cancer Biol. 17, 317–329 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Thomas, S. et al. Human T cells expressing affinity-matured TCR display accelerated responses but fail to recognize low density of MHC-peptide antigen. Blood 118, 319–329 (2011).

    CAS  PubMed  Google Scholar 

  126. Engels, B., Chervin, A. S., Sant, A. J., Kranz, D. M. & Schreiber, H. Long-term persistence of CD4(+) but rapid disappearance of CD8(+) T cells expressing an MHC class I-restricted TCR of nanomolar affinity. Mol. Ther. 20, 652–660 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Schmid, D. A. et al. Evidence for a TCR affinity threshold delimiting maximal CD8 T cell function. J. Immunol. 184, 4936–4946 (2010).

    CAS  PubMed  Google Scholar 

  128. Galvez, J., Galvez, J. J. & Garcia-Penarrubia, P. Is TCR/pMHC affinity a good estimate of the T-cell response? An answer based on predictions from 12 phenotypic models. Front. Immunol. 10, 349 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Oliveira, G. et al. Phenotype, specificity and avidity of antitumour CD8(+) T cells in melanoma. Nature 596, 119–125 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Aleksic, M. et al. Different affinity windows for virus and cancer-specific T-cell receptors: implications for therapeutic strategies. Eur. J. Immunol. 42, 3174–3179 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Hoffmann, M. M. & Slansky, J. E. T-cell receptor affinity in the age of cancer immunotherapy. Mol. Carcinog. 59, 862–870 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Smith, S. N. et al. Changing the peptide specificity of a human T-cell receptor by directed evolution. Nat. Commun. 5, 5223 (2014).

    CAS  PubMed  Google Scholar 

  133. Bassan, D. et al. Avidity optimization of a MAGE-A1-specific TCR with somatic hypermutation. Eur. J. Immunol. 51, 1505–1518 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Hsiue, E. H. et al. Targeting a neoantigen derived from a common TP53 mutation. Science https://doi.org/10.1126/science.abc8697 (2021).

  135. Douglass, J. et al. Bispecific antibodies targeting mutant RAS neoantigens. Sci. Immunol. https://doi.org/10.1126/sciimmunol.abd5515 (2021).

  136. Hwang, M. S. et al. Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens. Nat. Commun. 12, 5271 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Poorebrahim, M. et al. TCR-like CARs and TCR-CARs targeting neoepitopes: an emerging potential. Cancer Gene Ther. 28, 581–589 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Poole, A. et al. Therapeutic high affinity T cell receptor targeting a KRASG12D cancer neoantigen. Nat. Commun. 13, 5333 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Gonzalez, P. A. et al. T cell receptor binding kinetics required for T cell activation depend on the density of cognate ligand on the antigen-presenting cell. Proc. Natl Acad. Sci. USA 102, 4824–4829 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Engels, B. et al. Relapse or eradication of cancer is predicted by peptide-major histocompatibility complex affinity. Cancer Cell 23, 516–526 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Yu, Z. et al. Poor immunogenicity of a self/tumor antigen derives from peptide-MHC-I instability and is independent of tolerance. J. Clin. Invest. 114, 551–559 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Purbhoo, M. A. et al. Quantifying and imaging NY-ESO-1/LAGE-1-derived epitopes on tumor cells using high affinity T cell receptors. J. Immunol. 176, 7308–7316 (2006).

    CAS  PubMed  Google Scholar 

  143. Stopfer, L. E. et al. Absolute quantification of tumor antigens using embedded MHC-I isotopologue calibrants. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2111173118 (2021).

  144. Apavaloaei, A., Hardy, M. P., Thibault, P. & Perreault, C. The origin and immune recognition of tumor-specific antigens. Cancers https://doi.org/10.3390/cancers12092607 (2020).

  145. Ashrafi, G. H., Haghshenas, M. R., Marchetti, B., O’Brien, P. M. & Campo, M. S. E5 protein of human papillomavirus type 16 selectively downregulates surface HLA class I. Int. J. Cancer 113, 276–283 (2005).

    CAS  PubMed  Google Scholar 

  146. Jaeger, A. M. et al. Deciphering the tumor-specific immunopeptidome in vivo with genetically engineered mouse models. Nature https://doi.org/10.1038/s41586-022-04839-2 (2022).

  147. Norbury, C. C. et al. CD8+ T cell cross-priming via transfer of proteasome substrates. Science 304, 1318–1321 (2004).

    CAS  PubMed  Google Scholar 

  148. Westcott, P. M. K. et al. Low neoantigen expression and poor T-cell priming underlie early immune escape in colorectal cancer. Nat. Cancer 2, 1071–1085 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Wolf, Y. & Samuels, Y. Intratumor heterogeneity and antitumor immunity shape one another bidirectionally. Clin. Cancer Res. 28, 2994–3001 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Gejman, R. S. et al. Rejection of immunogenic tumor clones is limited by clonal fraction. eLife https://doi.org/10.7554/elife.41090 (2018).

  151. McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Wolf, Y. et al. UVB-induced tumor heterogeneity diminishes immune response in melanoma. Cell. 179, 219–235 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Rosenthal, R. et al. Neoantigen-directed immune escape in lung cancer evolution. Nature 567, 479–485 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Lowery, F. J. et al. Molecular signatures of antitumor neoantigen-reactive T cells from metastatic human cancers. Science 375, 877–884 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Caushi, J. X. et al. Author Correction: Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers. Nature https://doi.org/10.1038/s41586-021-03893-6 (2021).

  156. Caushi, J. X. et al. Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers. Nature 596, 126–132 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Parkhurst, M. R. et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol. Ther. 19, 620–626 (2011).

    CAS  PubMed  Google Scholar 

  158. Hunder, N. N. et al. Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N. Engl. J. Med. 358, 2698–2703 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Robbins, P. F. et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J. Clin. Oncol. 29, 917 (2011).

    PubMed  PubMed Central  Google Scholar 

  160. Anon. T cells targeting MAGE-A4 shrink tumors. Cancer Discov. https://doi.org/10.1158/2159-8290.CD-NB2020-059 (2020).

  161. Rapoport, A. P. et al. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat. Med. 21, 914–921 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Klippel, Z. K. et al. Immune escape from NY-ESO-1-specific T-cell therapy via loss of heterozygosity in the MHC. Gene Ther. 21, 337–342 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Lu, Y. C. et al. Treatment of patients with metastatic cancer using a major histocompatibility complex class II-restricted T-cell receptor targeting the cancer germline antigen MAGE-A3. J. Clin. Oncol. 35, 3322–3329 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Chodon, T. et al. Adoptive transfer of MART-1 T-cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma. Clin. Cancer Res. 20, 2457–2465 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Sahin, U. et al. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. Nature 585, 107–112 (2020).

    CAS  PubMed  Google Scholar 

  166. Stevanovic, S. et al. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science 356, 200–205 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. van den Berg, J. H. et al. Tumor infiltrating lymphocytes (TIL) therapy in metastatic melanoma: boosting of neoantigen-specific T cell reactivity and long-term follow-up. J. Immunother. Cancer https://doi.org/10.1136/jitc-2020-000848 (2020).

  168. van Rooij, N. et al. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J. Clin. Oncol. 31, e439–e442 (2013).

    PubMed  Google Scholar 

  169. Veatch, J. R. et al. Mobilization of pre-existing polyclonal T cells specific to neoantigens but not self-antigens during treatment of a patient with melanoma with bempegaldesleukin and nivolumab. J. Immunother. Cancer 8, e001591 (2020).

    PubMed  PubMed Central  Google Scholar 

  170. Zacharakis, N. et al. Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer. Nat. Med. 24, 724–730 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Shemesh, C. S. et al. Personalized cancer vaccines: clinical landscape, challenges, and opportunities. Mol. Ther. 29, 555–570 (2021).

    CAS  PubMed  Google Scholar 

  172. Ott, P. A. et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217–221 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Sahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222–226 (2017).

    CAS  PubMed  Google Scholar 

  174. Platten, M. et al. A vaccine targeting mutant IDH1 in newly diagnosed glioma. Nature 592, 463–468 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Kim, S. P. et al. Adoptive cellular therapy with autologous tumor-infiltrating lymphocytes and T-cell Receptor-engineered T cells targeting common p53 neoantigens in human solid tumors. Cancer Immunol. Res. https://doi.org/10.1158/2326-6066.CIR-22-0040 (2022).

  176. Mo, Y. et al. Prophylactic and therapeutic HPV vaccines: current scenario and perspectives. Front. Cell Infect. Microbiol. 12, 909223 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Smith, J. A. et al. SMCX and components of the TIP60 complex contribute to E2 regulation of the HPV E6/E7 promoter. Virology 468-470, 311–321 (2014).

    CAS  PubMed  Google Scholar 

  178. Basu, P. et al. A Randomized Phase 2 Study of ADXS11-001 Listeria monocytogenes-Listeriolysin O Immunotherapy With or Without Cisplatin in Treatment of Advanced Cervical Cancer. Int. J. Gynecol. Cancer 28, 764–772 (2018).

    PubMed  PubMed Central  Google Scholar 

  179. Kawana, K. et al. Oral vaccination against HPV E7 for treatment of cervical intraepithelial neoplasia grade 3 (CIN3) elicits E7-specific mucosal immunity in the cervix of CIN3 patients. Vaccine 32, 6233–6239 (2014).

    CAS  PubMed  Google Scholar 

  180. Ikeda, Y. et al. A placebo-controlled, double-blind randomized (phase IIB) trial of oral administration with HPV16 E7-expressing Lactobacillus, GLBL101c, for the treatment of cervical intraepithelial neoplasia grade 2 (CIN2). Vaccines https://doi.org/10.3390/vaccines9040329 (2021).

  181. Massarelli, E. et al. Combining immune checkpoint blockade and tumor-specific vaccine for patients with incurable human papillomavirus 16-related cancer: a phase 2 clinical trial. JAMA Oncol. 5, 67–73 (2019).

    PubMed  Google Scholar 

  182. Melief, C. J. M. et al. Strong vaccine responses during chemotherapy are associated with prolonged cancer survival. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aaz8235 (2020).

  183. Choi, Y. J. et al. A phase II, prospective, randomized, multicenter, open-label study of GX-188E, an HPV DNA Vaccine, in patients with cervical intraepithelial neoplasia 3. Clin. Cancer Res. 26, 1616–1623 (2020).

    CAS  PubMed  Google Scholar 

  184. Alvarez, R. D. et al. A pilot study of pNGVL4a-CRT/E7(detox) for the treatment of patients with HPV16+ cervical intraepithelial neoplasia 2/3 (CIN2/3). Gynecol. Oncol. 140, 245–252 (2016).

    CAS  PubMed  Google Scholar 

  185. Stevanovic, S. et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. J. Clin. Oncol. 33, 1543–1550 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Chow, J. C., Ngan, R. K., Cheung, K. M. & Cho, W. C. Immunotherapeutic approaches in nasopharyngeal carcinoma. Expert Opin. Biol. Ther. 19, 1165–1172 (2019).

    CAS  PubMed  Google Scholar 

  187. Burger, M. L. et al. Antigen dominance hierarchies shape TCF1(+) progenitor CD8 T cell phenotypes in tumors. Cell 184, 4996–5014 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Carreno, B. M. et al. Cancer immunotherapy. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science 348, 803–808 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Kreiter, S. et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520, 692–696 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Hu, Z. et al. Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma. Nat. Med. 27, 515–525 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Hilf, N. et al. Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature 565, 240–245 (2019).

    CAS  PubMed  Google Scholar 

  192. Keskin, D. B. et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 565, 234–239 (2019).

    CAS  PubMed  Google Scholar 

  193. Ott, P. A. et al. A phase Ib trial of personalized neoantigen therapy plus anti-PD-1 in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. Cell 183, 347–362 (2020).

    CAS  PubMed  Google Scholar 

  194. Cafri, G. et al. mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer. J. Clin. Invest. 130, 5976–5988 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Gross, L. Intradermal immunization of C3H mice against a sarcoma that originated in an animal of the same line. Cancer Res. 3, 326–333 (1943).

    Google Scholar 

  196. Miller, J. F. & Mitchell, G. F. The thymus and the precursors of antigen reactive cells. Nature 216, 659–663 (1967).

    CAS  PubMed  Google Scholar 

  197. Cerottini, J. C. & Brunner, K. T. Cell-mediated cytotoxicity, allograft rejection, and tumor immunity. Adv. Immunol. 18, 67–132 (1974).

    CAS  PubMed  Google Scholar 

  198. Rosenberg, S. A. et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N. Engl. J. Med. 319, 1676–1680 (1988).

    CAS  PubMed  Google Scholar 

  199. De Plaen, E. et al. Immunogenic (tum-) variants of mouse tumor P815: cloning of the gene of tum-antigen P91A and identification of the tum-mutation. Proc. Natl Acad. Sci. USA 85, 2274–2278 (1988).

    PubMed  PubMed Central  Google Scholar 

  200. Traversari, C. et al. A nonapeptide encoded by human gene MAGE-1 is recognized on HLA-A1 by cytolytic T lymphocytes directed against tumor antigen MZ2-E. J. Exp. Med. 176, 1453–1457 (1992).

    CAS  PubMed  Google Scholar 

  201. Fisk, B., Blevins, T. L., Wharton, J. T. & Ioannides, C. G. Identification of an immunodominant peptide of HER-2/neu protooncogene recognized by ovarian tumor-specific cytotoxic T lymphocyte lines. J. Exp. Med. 181, 2109–2117 (1995).

    CAS  PubMed  Google Scholar 

  202. Acres, B. & Limacher, J.-M. MUC1 as a target antigen for cancer immunotherapy. Expert Rev. Vaccines 4, 493–502 (2005).

    CAS  PubMed  Google Scholar 

  203. Wood, L. D. et al. The genomic landscapes of human breast and colorectal cancers. Science 318, 1108–1113 (2007).

    CAS  PubMed  Google Scholar 

  204. Cheever, M. A. & Higano, C. S. PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine. Clin. Cancer Res. 17, 3520–3526 (2011).

    PubMed  Google Scholar 

  205. Fellner, C. Ipilimumab (yervoy) prolongs survival in advanced melanoma: serious side effects and a hefty price tag may limit its use. P T 37, 503–530 (2012).

    PubMed  PubMed Central  Google Scholar 

  206. Raedler, L. A. Keytruda (pembrolizumab): first PD-1 Inhibitor approved for previously treated unresectable or metastatic melanoma. Am. Health Drug Benefits 8, 96–100 (2015).

    PubMed  PubMed Central  Google Scholar 

  207. Raedler, L. A. Opdivo (nivolumab): second PD-1 inhibitor receives FDA approval for unresectable or metastatic melanoma. Am. Health Drug Benefits 8, 180–183 (2015).

  208. Rosenberg, S. A. et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res. 17, 4550–4557 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Rosenberg, S. A. & Restifo, N. P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Sahin, U. & Tureci, O. Personalized vaccines for cancer immunotherapy. Science 359, 1355–1360 (2018).

    CAS  PubMed  Google Scholar 

  211. Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Wei, S. C., Duffy, C. R. & Allison, J. P. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 8, 1069–1086 (2018).

    PubMed  Google Scholar 

  213. Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N. Engl. J. Med. 383, 2603–2615 (2020).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Y.S. is supported by the Israel Science Foundation (grant no. 696/17), the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 770854), Melanoma Research Alliance (622106), Israel Science Foundation (696/17), the Knell Family and the Hamburger Family. Y.W. is supported by a Melanoma Research Alliance grant (937368), the Rosetrees Trust (MYIA\100002), a research grant from Pfizer and the Lemelbaum family. M.D. is supported by a grant of the German Research Foundation (DI 2359/1-1).

Author information

Authors and Affiliations

  1. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel

    Aviyah Peri & Yardena Samuels

  2. TRON – Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz gGmbH, Mainz, Germany

    Nadja Salomon, Sebastian Kreiter & Mustafa Diken

  3. Ella Lemelbaum Institute for Immuno-oncology and Skin Cancer, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel

    Yochai Wolf

  4. Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Yochai Wolf

Authors
  1. Aviyah Peri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nadja Salomon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yochai Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sebastian Kreiter
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mustafa Diken
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yardena Samuels
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yochai Wolf, Sebastian Kreiter, Mustafa Diken or Yardena Samuels.

Ethics declarations

Competing interests

M.D. and S.K. are authors of studies mentioned in this review. A.P. and N.S. declare no competing interests. Y.W. declares a research grant from Pfizer and is an author of studies mentioned in this review.

Peer review

Peer review information

Nature Cancer thanks the anonymous reviewers for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Peri, A., Salomon, N., Wolf, Y. et al. The landscape of T cell antigens for cancer immunotherapy. Nat Cancer 4, 937–954 (2023). https://doi.org/10.1038/s43018-023-00588-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s43018-023-00588-x

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer