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:

Cancer immune evasion, immunoediting and intratumour heterogeneity

Abstract

Cancers can avoid immune-mediated elimination by acquiring traits that disrupt antitumour immunity. These mechanisms of immune evasion are selected and reinforced during tumour evolution under immune pressure. Some immunogenic subclones are effectively eliminated by antitumour T cell responses (a process known as immunoediting), which results in a clonally selected tumour. Other cancer cells arise to resist immunoediting, which leads to a tumour that includes several distinct cancer cell populations (referred to as intratumour heterogeneity (ITH)). Tumours with high ITH are associated with poor patient outcomes and a lack of responsiveness to immune checkpoint blockade therapy. In this Review, we discuss the different ways that cancer cells evade the immune system and how these mechanisms impact immunoediting and tumour evolution. We also describe how subclonal antigen presentation in tumours with high ITH can result in immune evasion.

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

Access options

Buy this article

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

Fig. 1: Immunoediting, immune evasion and intratumour heterogeneity.
Fig. 2: Cancer cell-intrinsic immune evasion mechanisms.
Fig. 3: Tissue-specific immune evasion.
Fig. 4: Reduced antitumour immunity in the context of subclonal antigen presentation.

Similar content being viewed by others

References

  1. Dunn, G. P., Old, L. J. & Schreiber, R. D. The three Es of cancer immunoediting. Annu. Rev. Immunol. 22, 329–360 (2004). This review refines previous concepts into the cancer immunoediting hypothesis, highlighting the role of the immune system in suppressing tumour growth and in shaping tumour immunogenicity.

    Article  CAS  PubMed  Google Scholar 

  2. Burnet, F. M. The concept of immunological surveillance. Prog. Exp. Tumor Res. 13, 1–27 (1970).

    Article  CAS  PubMed  Google Scholar 

  3. Boon, T. & van der Bruggen, P. Human tumor antigens recognized by T lymphocytes. J. Exp. Med. 183, 725–729 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Shankaran, V. et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–1111 (2001). This study shows that the adaptive immune response can prevent tumour formation or lead to a selection of tumour cells with reduced immunogenicity.

    Article  CAS  PubMed  Google Scholar 

  5. Monach, P. A., Meredith, S. C., Siegel, C. T. & Schreiber, H. A unique tumor antigen produced by a single amino acid substitution. Immunity 2, 45–59 (1995).

    Article  CAS  PubMed  Google Scholar 

  6. Grizzi, F. et al. Cancer-testis antigens and immunotherapy in the light of cancer complexity. Int. Rev. Immunol. 34, 143–153 (2015).

    Article  CAS  PubMed  Google Scholar 

  7. Łuksza, M. et al. Neoantigen quality predicts immunoediting in survivors of pancreatic cancer. Nature 606, 389–395 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Milo, I. et al. The immune system profoundly restricts intratumor genetic heterogeneity. Sci. Immunol. 3, eaat1435 (2018). This preclinical study shows that immune pressure reduces the diversity of genetic mutations and intratumour heterogeneity through the selective elimination of immunogenic tumour cells.

    Article  PubMed  Google Scholar 

  9. Dhanasekaran, R. et al. The MYC oncogene — the grand orchestrator of cancer growth and immune evasion. Nat. Rev. Clin. Oncol. 19, 23–36 (2022).

    Article  CAS  PubMed  Google Scholar 

  10. Kallingal, A., Olszewski, M., Maciejewska, N., Brankiewicz, W. & Baginski, M. Cancer immune escape: the role of antigen presentation machinery. J. Cancer Res. Clin. Oncol. 149, 8131–8141 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kim, S. H. et al. The COX2 effector microsomal PGE2 synthase 1 is a regulator of immunosuppression in cutaneous melanoma. Clin. Cancer Res. 25, 1650–1663 (2019).

    Article  CAS  PubMed  Google Scholar 

  12. Kohanbash, G. et al. Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas. J. Clin. Invest. 127, 1425–1437 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mellman, I., Chen, D. S., Powles, T. & Turley, S. J. The cancer-immunity cycle: indication, genotype, and immunotype. Immunity 56, 2188–2205 (2023).

    Article  CAS  PubMed  Google Scholar 

  16. McGranahan, N. & Swanton, C. Clonal heterogeneity and tumor evolution: past, present, and the future. Cell 168, 613–628 (2017).

    Article  CAS  PubMed  Google Scholar 

  17. Boström, M. & Larsson, E. Somatic mutation distribution across tumour cohorts provides a signal for positive selection in cancer. Nat. Commun. 13, 7023 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Zapata, L. et al. Immune selection determines tumor antigenicity and influences response to checkpoint inhibitors. Nat. Genet. 55, 451–460 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Davis, A., Gao, R. & Navin, N. Tumor evolution: linear, branching, neutral or punctuated? Biochim. Biophys. Acta Rev. Cancer 1867, 151–161 (2017).

    Article  CAS  PubMed  Google Scholar 

  20. Vendramin, R., Litchfield, K. & Swanton, C. Cancer evolution: Darwin and beyond. EMBO J. 40, e108389 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cindy Yang, S. Y. et al. Pan-cancer analysis of longitudinal metastatic tumors reveals genomic alterations and immune landscape dynamics associated with pembrolizumab sensitivity. Nat. Commun. 12, 5137 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Angelova, M. et al. Evolution of metastases in space and time under immune selection. Cell 175, 751–765.e16 (2018). In this longitudinal study of patients with colorectal cancer, branched evolution could be traced back to tumour subclones that evade the immune system owing to tumour-intrinsic and tumour-extrinsic mechanisms.

    Article  CAS  PubMed  Google Scholar 

  23. Jiménez-Sánchez, A. et al. Heterogeneous tumor-immune microenvironments among differentially growing metastases in an ovarian cancer patient. Cell 170, 927–938.e20 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Jiménez-Sánchez, A. et al. Unraveling tumor-immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy. Nat. Genet. 52, 582–593 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Litchfield, K. et al. Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition. Cell 184, 596–614.e14 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016). This seminal study demonstrates that the clonality of tumour neoantigens is linked to immune activity, patient outcomes and responsiveness to immune checkpoint blockade therapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. McDonald, K. A. et al. Tumor heterogeneity correlates with less immune response and worse survival in breast cancer patients. Ann. Surg. Oncol. 26, 2191–2199 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Nguyen, K. B. et al. Decoupled neoantigen cross-presentation by dendritic cells limits anti-tumor immunity against tumors with heterogeneous neoantigen expression. eLife 12, e85263 (2023). This study demonstrates that neoantigen heterogeneity in tumour cells is preserved in cross-presenting dendritic cells in the tumour-draining lymph nodes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wolf, A. M. et al. Increase of regulatory T cells in the peripheral blood of cancer patients. Clin. Cancer Res. 9, 606–612 (2003).

    PubMed  Google Scholar 

  30. Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015).

    Article  CAS  PubMed  Google Scholar 

  31. Meyer, M. A. et al. Breast and pancreatic cancer interrupt IRF8-dependent dendritic cell development to overcome immune surveillance. Nat. Commun. 9, 1250 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Lin, J. H. et al. Type 1 conventional dendritic cells are systemically dysregulated early in pancreatic carcinogenesis. J. Exp. Med. 217, e20190673 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Casbon, A. J. et al. Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc. Natl Acad. Sci. USA 112, E566–E575 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Joyce, J. A. & Fearon, D. T. T cell exclusion, immune privilege, and the tumor microenvironment. Science 348, 74–80 (2015).

    Article  CAS  PubMed  Google Scholar 

  35. Xue, R. et al. Liver tumour immune microenvironment subtypes and neutrophil heterogeneity. Nature 612, 141–147 (2022).

    Article  CAS  PubMed  Google Scholar 

  36. Yi, M., Niu, M., Xu, L., Luo, S. & Wu, K. Regulation of PD-L1 expression in the tumor microenvironment. J. Hematol. Oncol. 14, 10 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. McGranahan, N. et al. Allele-specific HLA loss and immune escape in lung cancer evolution. Cell 171, 1259–1271.e11 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Luke, J. J., Bao, R., Sweis, R. F., Spranger, S. & Gajewski, T. F. WNT/β-catenin pathway activation correlates with immune exclusion across human cancers. Clin. Cancer Res. 25, 3074–3083 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zagorulya, M. et al. Tissue-specific abundance of interferon-gamma drives regulatory T cells to restrain DC1-mediated priming of cytotoxic T cells against lung cancer. Immunity 56, 386–405.e10 (2023). This study demonstrates that tissue-specific differences in the activation status of regulatory T cells affect the priming of tumour-reactive T cells in the lymph node by reducing the stimulatory potential of cross-presenting dendritic cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dijkstra, K. K., Wu, Y. & Swanton, C. The effects of clonal heterogeneity on cancer immunosurveillance. Ann. Rev. Cancer Biol. 7, 131–147 (2023).

    Article  Google Scholar 

  41. Pozzi, L. A., Maciaszek, J. W. & Rock, K. L. Both dendritic cells and macrophages can stimulate naive CD8 T cells in vivo to proliferate, develop effector function, and differentiate into memory cells. J. Immunol. 175, 2071–2081 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Anderson, K. G., Stromnes, I. M. & Greenberg, P. D. Obstacles posed by the tumor microenvironment to T cell activity: a case for synergistic therapies. Cancer Cell 31, 311–325 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ataide, M. A. et al. Lymphatic migration of unconventional T cells promotes site-specific immunity in distinct lymph nodes. Immunity 55, 1813–1828.e9 (2022). This elegant study shows that unconventional T cells that migrate from the tissue determine the immune environment in the draining lymph node and are key determinants of site-specific immunity.

    Article  CAS  PubMed  Google Scholar 

  44. Blank, C. U. et al. Defining ‘T cell exhaustion’. Nat. Rev. Immunol. 19, 665–674 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang, X., Teng, F., Kong, L. & Yu, J. PD-L1 expression in human cancers and its association with clinical outcomes. Onco Targets Ther. 9, 5023–5039 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lin, A. & Yan, W. H. Human leukocyte antigen-G (HLA-G) expression in cancers: roles in immune evasion, metastasis and target for therapy. Mol. Med. 21, 782–791 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Taguchi, K. et al. Tumor endothelial cell-mediated antigen-specific T-cell suppression via the PD-1/PD-L1 pathway. Mol. Cancer Res. 18, 1427–1440 (2020).

    Article  CAS  PubMed  Google Scholar 

  48. Fang, J. et al. Exploring the crosstalk between endothelial cells, immune cells, and immune checkpoints in the tumor microenvironment: new insights and therapeutic implications. Cell Death Dis. 14, 586 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Shinchi, Y. et al. The expression of PD-1 ligand 1 on macrophages and its clinical impacts and mechanisms in lung adenocarcinoma. Cancer Immunol. Immunother. 71, 2645–2661 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lenz, H. J. et al. First-line nivolumab plus low-dose ipilimumab for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study. J. Clin. Oncol. 40, 161–170 (2022).

    Article  CAS  PubMed  Google Scholar 

  52. Hellmann, M. D. et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N. Engl. J. Med. 381, 2020–2031 (2019).

    Article  CAS  PubMed  Google Scholar 

  53. Motz, G. T. et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat. Med. 20, 607–615 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Strand, S. et al. Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells — a mechanism of immune evasion? Nat. Med. 2, 1361–1366 (1996).

    Article  CAS  PubMed  Google Scholar 

  55. Christofides, A. et al. The complex role of tumor-infiltrating macrophages. Nat. Immunol. 23, 1148–1156 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hedrick, C. C. & Malanchi, I. Neutrophils in cancer: heterogeneous and multifaceted. Nat. Rev. Immunol. 22, 173–187 (2022).

    Article  CAS  PubMed  Google Scholar 

  57. Donadon, M. et al. Macrophage morphology correlates with single-cell diversity and prognosis in colorectal liver metastasis. J. Exp. Med. 217, e20191847 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. van Elsas, M. J. et al. Immunotherapy-activated T cells recruit and skew late-stage activated M1-like macrophages that are critical for therapeutic efficacy. Cancer Cell 42, 1032–1050.e10 (2024).

    Article  PubMed  Google Scholar 

  59. Zou, Z., Lin, H., Li, M. & Lin, B. Tumor-associated macrophage polarization in the inflammatory tumor microenvironment. Front. Oncol. 13, 1103149 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Huber, R. et al. Tumour hypoxia promotes melanoma growth and metastasis via high mobility group box-1 and M2-like macrophages. Sci. Rep. 6, 29914 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Bloch, O. et al. Gliomas promote immunosuppression through induction of B7-H1 expression in tumor-associated macrophages. Clin. Cancer Res. 19, 3165–3175 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hwang, I. et al. Tumor-associated macrophage, angiogenesis and lymphangiogenesis markers predict prognosis of non-small cell lung cancer patients. J. Transl. Med. 18, 443 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bonde, A. K., Tischler, V., Kumar, S., Soltermann, A. & Schwendener, R. A. Intratumoral macrophages contribute to epithelial–mesenchymal transition in solid tumors. BMC Cancer 12, 35 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Qian, B. Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Gettinger, S. et al. Impaired HLA class I antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer. Cancer Discov. 7, 1420–1435 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Cromme, F. V. et al. Loss of transporter protein, encoded by the TAP-1 gene, is highly correlated with loss of HLA expression in cervical carcinomas. J. Exp. Med. 179, 335–340 (1994).

    Article  CAS  PubMed  Google Scholar 

  67. Zaretsky, J. M. et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375, 819–829 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Shukla, S. A. et al. Comprehensive analysis of cancer-associated somatic mutations in class I HLA genes. Nat. Biotechnol. 33, 1152–1158 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Nie, Y. et al. DNA hypermethylation is a mechanism for loss of expression of the HLA class I genes in human esophageal squamous cell carcinomas. Carcinogenesis 22, 1615–1623 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Jiang, Q. et al. Downregulation of tapasin expression in primary human oral squamous cell carcinoma: association with clinical outcome. Tumor Biol. 31, 451–459 (2010).

    Article  CAS  Google Scholar 

  71. Bicknell, D. C., Kaklamanis, L., Hampson, R., Bodmer, W. F. & Karran, P. Selection for ß2-microglobulin mutation in mismatch repair-defective colorectal carcinomas. Curr. Biol. 6, 1695–1697 (1996).

    Article  CAS  PubMed  Google Scholar 

  72. Raulet, D. H. Interplay of natural killer cells and their receptors with the adaptive immune response. Nat. Immunol. 5, 996–1002 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Filip, I. et al. Pervasiveness of HLA allele-specific expression loss across tumor types. Genome Med. 15, 8 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Michelakos, T. et al. Differential role of HLA-A and HLA-B, C expression levels as prognostic markers in colon and rectal cancer. J. Immunother. Cancer 10, e004115 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Watson, N. F. et al. Immunosurveillance is active in colorectal cancer as downregulation but not complete loss of MHC class I expression correlates with a poor prognosis. Int. J. Cancer 118, 6–10 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Grasso, C. S. et al. Conserved interferon-γ signaling drives clinical response to immune checkpoint blockade therapy in melanoma. Cancer Cell 39, 122 (2021).

    Article  CAS  PubMed  Google Scholar 

  77. Liao, W. et al. KRAS–IRF2 axis drives immune suppression and immune therapy resistance in colorectal cancer. Cancer Cell 35, 559–572.e7 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Alspach, E. et al. MHC-II neoantigens shape tumour immunity and response to immunotherapy. Nature 574, 696–701 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ferris, S. T. et al. cDC1 prime and are licensed by CD4+ T cells to induce anti-tumour immunity. Nature 584, 624–629 (2020). This work shows that cDC1s orchestrate the crosstalk between CD8+ and CD4+ T cell responses that is required for optimal antitumour immune responses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Quezada, S. A. et al. Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. J. Exp. Med. 207, 637–650 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Linnemann, C. et al. High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma. Nat. Med. 21, 81–85 (2015).

    Article  CAS  PubMed  Google Scholar 

  82. Reed, C. M., Cresce, N. D., Mauldin, I. S., Slingluff, C. L. Jr. & Olson, W. C. Vaccination with melanoma helper peptides induces antibody responses associated with improved overall survival. Clin. Cancer Res. 21, 3879–3887 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wolf, S. P. et al. One CD4+ TCR and one CD8+ TCR targeting autochthonous neoantigens are essential and sufficient for tumor eradication. Clin. Cancer Res. 30, 1642–1654 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Rojas, L. A. et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 618, 144–150 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Huff, A. L. et al. CD4 T cell-activating neoantigens enhance personalized cancer vaccine efficacy. JCI Insight 8, e174027 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Cheung, A. F., Dupage, M. J., Dong, H. K., Chen, J. & Jacks, T. Regulated expression of a tumor-associated antigen reveals multiple levels of T-cell tolerance in a mouse model of lung cancer. Cancer Res. 68, 9459–9468 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Yan, J. et al. In vivo role of ER-associated peptidase activity in tailoring peptides for presentation by MHC class Ia and class Ib molecules. J. Exp. Med. 203, 647–659 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Daniel, B. et al. Divergent clonal differentiation trajectories of T cell exhaustion. Nat. Immunol. 23, 1614–1627 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kohli, K., Pillarisetty, V. G. & Kim, T. S. Key chemokines direct migration of immune cells in solid tumors. Cancer Gene Ther. 29, 10–21 (2022).

    Article  CAS  PubMed  Google Scholar 

  90. 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.e4 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Mikucki, M. E. et al. Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints. Nat. Commun. 6, 7458 (2015).

    Article  CAS  PubMed  Google Scholar 

  92. Chheda, Z. S., Sharma, R. K., Jala, V. R., Luster, A. D. & Haribabu, B. Chemoattractant receptors BLT1 and CXCR3 regulate antitumor immunity by facilitating CD8+ T cell migration into tumors. J. Immunol. 197, 2016–2026 (2016).

    Article  CAS  PubMed  Google Scholar 

  93. Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203–213 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Mlecnik, B. et al. Biomolecular network reconstruction identifies T-cell homing factors associated with survival in colorectal cancer. Gastroenterology 138, 1429–1440 (2010).

    Article  CAS  PubMed  Google Scholar 

  95. Harlin, H. et al. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 69, 3077–3085 (2009).

    Article  CAS  PubMed  Google Scholar 

  96. Chow, M. T. et al. Intratumoral activity of the CXCR3 chemokine system is required for the efficacy of anti-PD-1 therapy. Immunity 50, 1498–1512.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Weenink, B. et al. Low-grade glioma harbors few CD8 T cells, which is accompanied by decreased expression of chemo-attractants, not immunogenic antigens. Sci. Rep. 9, 14643 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Sugiyama, E. et al. Blockade of EGFR improves responsiveness to PD-1 blockade in EGFR-mutated non-small cell lung cancer. Sci. Immunol. 5, eaav3937 (2020).

    Article  CAS  PubMed  Google Scholar 

  99. Zingg, D. et al. The histone methyltransferase Ezh2 controls mechanisms of adaptive resistance to tumor immunotherapy. Cell Rep. 20, 854–867 (2017).

    Article  CAS  PubMed  Google Scholar 

  100. Kitajima, S. et al. Suppression of STING associated with LKB1 loss in KRAS-driven lung cancer. Cancer Discov. 9, 34–45 (2019).

    Article  CAS  PubMed  Google Scholar 

  101. Vianello, F. et al. Murine B16 melanomas expressing high levels of the chemokine stromal-derived factor-1/CXCL12 induce tumor-specific T cell chemorepulsion and escape from immune control. J. Immunol. 176, 2902–2914 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Sun, X. et al. CXCL12/CXCR4/CXCR7 chemokine axis and cancer progression. Cancer Metastasis Rev. 29, 709–722 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Costa, A. et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell 33, 463–479.e10 (2018).

    Article  CAS  PubMed  Google Scholar 

  104. Righi, E. et al. CXCL12/CXCR4 blockade induces multimodal antitumor effects that prolong survival in an immunocompetent mouse model of ovarian cancer. Cancer Res. 71, 5522–5534 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Fukumura, D., Kloepper, J., Amoozgar, Z., Duda, D. G. & Jain, R. K. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat. Rev. Clin. Oncol. 15, 325–340 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Huinen, Z. R., Huijbers, E. J. M., van Beijnum, J. R., Nowak-Sliwinska, P. & Griffioen, A. W. Anti-angiogenic agents — overcoming tumour endothelial cell anergy and improving immunotherapy outcomes. Nat. Rev. Clin. Oncol. 18, 527–540 (2021).

    Article  PubMed  Google Scholar 

  107. Lin, Z. et al. PTEN loss correlates with T cell exclusion across human cancers. BMC Cancer 21, 429 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Huang, H. et al. VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-κB-induced endothelial activation. FASEB J. 29, 227–238 (2015).

    Article  CAS  PubMed  Google Scholar 

  109. George, S. et al. Loss of PTEN is associated with resistance to anti-PD-1 checkpoint blockade therapy in metastatic uterine leiomyosarcoma. Immunity 46, 197–204 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kwon, J. & Bakhoum, S. F. The cytosolic DNA-sensing cGAS–STING pathway in cancer. Cancer Discov. 10, 26–39 (2020).

    Article  CAS  PubMed  Google Scholar 

  111. Torres-Mejia, E. et al. Lung cancer-intrinsic SOX2 expression mediates resistance to checkpoint blockade therapy by inducing Treg-dependent CD8+ T cell exclusion. Preprint at bioRxiv https://doi.org/10.1101/2023.09.06.556520 (2023).

  112. Tjomsland, V. et al. The desmoplastic stroma plays an essential role in the accumulation and modulation of infiltrated immune cells in pancreatic adenocarcinoma. Clin. Dev. Immunol. 2011, 212810 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Akimoto, N. et al. Desmoplastic reaction, immune cell response, and prognosis in colorectal cancer. Front. Immunol. 13, 840198 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Hammerl, D. et al. Spatial immunophenotypes predict response to anti-PD1 treatment and capture distinct paths of T cell evasion in triple negative breast cancer. Nat. Commun. 12, 5668 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Salmon, H. et al. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J. Clin. Invest. 122, 899–910 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Chen, Y., McAndrews, K. M. & Kalluri, R. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat. Rev. Clin. Oncol. 18, 792–804 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Risom, T. et al. Transition to invasive breast cancer is associated with progressive changes in the structure and composition of tumor stroma. Cell 185, 299–310.e18 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Gibson, S. V. et al. Everybody needs good neighbours: the progressive DCIS microenvironment. Trends Cancer 9, 326–338 (2023).

    Article  CAS  PubMed  Google Scholar 

  120. Yoon, H. et al. TGF-β1-mediated transition of resident fibroblasts to cancer-associated fibroblasts promotes cancer metastasis in gastrointestinal stromal tumor. Oncogenesis 10, 13 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Ran, X. et al. Low intratumor heterogeneity correlates with increased response to PD-1 blockade in renal cell carcinoma. Ther. Adv. Med. Oncol. 12, 1758835920977117 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Del Prete, A. et al. Dendritic cell subsets in cancer immunity and tumor antigen sensing. Cell. Mol. Immunol. 20, 432–447 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Schietinger, A. et al. Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity 45, 389–401 (2016). Making use of an inducible liver cancer mouse model, this study shows that tumour-specific T cell dysfunction can occur early during tumorigenesis and is subsequently imprinted through persistent antigen exposure.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Ruiz de Galarreta, M. et al. β-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discov. 9, 1124–1141 (2019).

    Article  CAS  PubMed  Google Scholar 

  125. Yousef, A. et al. Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma. npj Precis. Oncol. 8, 27 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Prior, I. A., Lewis, P. D. & Mattos, C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 72, 2457–2467 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Lemieux, E., Cagnol, S., Beaudry, K., Carrier, J. & Rivard, N. Oncogenic KRAS signalling promotes the Wnt/β-catenin pathway through LRP6 in colorectal cancer. Oncogene 34, 4914–4927 (2015).

    Article  CAS  PubMed  Google Scholar 

  128. Bell, C. R. et al. Chemotherapy-induced COX-2 upregulation by cancer cells defines their inflammatory properties and limits the efficacy of chemoimmunotherapy combinations. Nat. Commun. 13, 2063 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Zagorulya, M. & Spranger, S. Once upon a prime: DCs shape cancer immunity. Trends Cancer 9, 172–184 (2023).

    Article  PubMed  Google Scholar 

  130. Jansen, C. S. et al. An intra-tumoral niche maintains and differentiates stem-like CD8 T cells. Nature 576, 465–470 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Pelka, K. et al. Spatially organized multicellular immune hubs in human colorectal cancer. Cell 184, 4734–4752.e20 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Cleary, A. S., Leonard, T. L., Gestl, S. A. & Gunther, E. J. Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers. Nature 508, 113–117 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Calbo, J. et al. A functional role for tumor cell heterogeneity in a mouse model of small cell lung cancer. Cancer Cell 19, 244–256 (2011).

    Article  CAS  PubMed  Google Scholar 

  134. Janiszewska, M. et al. Subclonal cooperation drives metastasis by modulating local and systemic immune microenvironments. Nat. Cell Biol. 21, 879–888 (2019). This study shows a functional cooperation of minor breast cancer subclones that promote dissemination of polyclonal metastatic tumours that are composed of driver and neutral subclones.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Kacar, Z. et al. Characterization of tumor evolution by functional clonality and phylogenetics in hepatocellular carcinoma. Commun. Biol. 7, 383 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Vázquez-García, I. et al. Ovarian cancer mutational processes drive site-specific immune evasion. Nature 612, 778–786 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Diamond, M. S., Lin, J. H. & Vonderheide, R. H. Site-dependent immune escape due to impaired dendritic cell cross-priming. Cancer Immunol. Res. 9, 877–890 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Correia, A. L. Locally sourced: site-specific immune barriers to metastasis. Nat. Rev. Immunol. 23, 522–538 (2023).

    Article  CAS  PubMed  Google Scholar 

  139. Dentro, S. C. et al. Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes. Cell 184, 2239–2254.e39 (2021). This pan-cancer resource analysis shows that most human cancers are subclonal and highlights the importance of intratumour heterogeneity and its drivers during tumour evolution.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Niederkorn, J. Y. See no evil, hear no evil, do no evil: the lessons of immune privilege. Nat. Immunol. 7, 354–359 (2006).

    Article  CAS  PubMed  Google Scholar 

  141. Abi-Hanna, D., Wakefield, D. & Watkins, S. HLA antigens in ocular tissues: I. In vivo expression in human eyes. Transplantation 45, 610–613 (1988).

    Article  CAS  PubMed  Google Scholar 

  142. Meinhardt, A. & Hedger, M. P. Immunological, paracrine and endocrine aspects of testicular immune privilege. Mol. Cell. Endocrinol. 335, 60–68 (2011).

    Article  CAS  PubMed  Google Scholar 

  143. Croese, T., Castellani, G. & Schwartz, M. Immune cell compartmentalization for brain surveillance and protection. Nat. Immunol. 22, 1083–1092 (2021).

    Article  CAS  PubMed  Google Scholar 

  144. Tu, S. M. et al. Intratumoral heterogeneity: role of differentiation in a potentially lethal phenotype of testicular cancer. Cancer 122, 1836–1843 (2016).

    Article  CAS  PubMed  Google Scholar 

  145. Durante, M. A. et al. Single-cell analysis reveals new evolutionary complexity in uveal melanoma. Nat. Commun. 11, 496 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Horton, B. L. et al. Lack of CD8+ T cell effector differentiation during priming mediates checkpoint blockade resistance in non-small cell lung cancer. Sci. Immunol. 6, eabi8800 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Tumeh, P. C. et al. Liver metastasis and treatment outcome with anti-PD-1 monoclonal antibody in patients with melanoma and NSCLC. Cancer Immunol. Res. 5, 417–424 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Bilen, M. A. et al. Sites of metastasis and association with clinical outcome in advanced stage cancer patients treated with immunotherapy. BMC Cancer 19, 857 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Tiegs, G. & Lohse, A. W. Immune tolerance: what is unique about the liver. J. Autoimmun. 34, 1–6 (2010).

    Article  CAS  PubMed  Google Scholar 

  150. Horst, A. K., Neumann, K., Diehl, L. & Tiegs, G. Modulation of liver tolerance by conventional and nonconventional antigen-presenting cells and regulatory immune cells. Cell. Mol. Immunol. 13, 277–292 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Sharma, S. K. et al. Pulmonary alveolar macrophages contribute to the premetastatic niche by suppressing antitumor T cell responses in the lungs. J. Immunol. 194, 5529–5538 (2015).

    Article  CAS  PubMed  Google Scholar 

  152. Liu, Y. et al. Tumor exosomal RNAs promote lung pre-metastatic niche formation by activating alveolar epithelial TLR3 to recruit neutrophils. Cancer Cell 30, 243–256 (2016).

    Article  PubMed  Google Scholar 

  153. Schuijs, M. J. et al. ILC2-driven innate immune checkpoint mechanism antagonizes NK cell antimetastatic function in the lung. Nat. Immunol. 21, 998–1009 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Coffelt, S. B. et al. IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis. Nature 522, 345–348 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Hiam-Galvez, K. J., Allen, B. M. & Spitzer, M. H. Systemic immunity in cancer. Nat. Rev. Cancer 21, 345–359 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Wu, W. C. et al. Circulating hematopoietic stem and progenitor cells are myeloid-biased in cancer patients. Proc. Natl Acad. Sci. USA 111, 4221–4226 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Bayne, L. J. et al. Tumor-derived granulocyte–macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 21, 822–835 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Zhou, J. et al. Enhanced frequency and potential mechanism of B regulatory cells in patients with lung cancer. J. Transl. Med. 12, 304 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Wang, W. W. et al. CD19+ CD24hiCD38hiBregs involved in downregulate helper T cells and upregulate regulatory T cells in gastric cancer. Oncotarget 6, 33486–33499 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Wang, L. et al. Connecting blood and intratumoral T(reg) cell activity in predicting future relapse in breast cancer. Nat. Immunol. 20, 1220–1230 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Allen, B. M. et al. Systemic dysfunction and plasticity of the immune macroenvironment in cancer models. Nat. Med. 26, 1125–1134 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Failli, A., Legitimo, A., Orsini, G., Romanini, A. & Consolini, R. Numerical defect of circulating dendritic cell subsets and defective dendritic cell generation from monocytes of patients with advanced melanoma. Cancer Lett. 337, 184–192 (2013).

    Article  CAS  PubMed  Google Scholar 

  163. Dominguez, C., McCampbell, K. K., David, J. M. & Palena, C. Neutralization of IL-8 decreases tumor PMN-MDSCs and reduces mesenchymalization of claudin-low triple-negative breast cancer. JCI Insight 2, e94296 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Wang, L. et al. IL6 signaling in peripheral blood T cells predicts clinical outcome in breast cancer. Cancer Res. 77, 1119–1126 (2017).

    Article  CAS  PubMed  Google Scholar 

  165. Verronèse, E. et al. Immune cell dysfunctions in breast cancer patients detected through whole blood multi-parametric flow cytometry assay. Oncoimmunology 5, e1100791 (2016).

    Article  PubMed  Google Scholar 

  166. Liu, Y. Y. et al. Characteristics and prognostic significance of profiling the peripheral blood T-cell receptor repertoire in patients with advanced lung cancer. Int. J. Cancer 145, 1423–1431 (2019).

    Article  CAS  PubMed  Google Scholar 

  167. Manuel, M. et al. Lymphopenia combined with low TCR diversity (divpenia) predicts poor overall survival in metastatic breast cancer patients. Oncoimmunology 1, 432–440 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Lee, K. A. et al. Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma. Nat. Med. 28, 535–544 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018).

    Article  CAS  PubMed  Google Scholar 

  170. Stein-Thoeringer, C. K. et al. A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy. Nat. Med. 29, 906–916 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Sepich-Poore, G. D. et al. The microbiome and human cancer. Science 371, eabc4552 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Marusyk, A., Janiszewska, M. & Polyak, K. Intratumor heterogeneity: the rosetta stone of therapy resistance. Cancer Cell 37, 471–484 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Westcott, P. M. K. et al. Mismatch repair deficiency is not sufficient to elicit tumor immunogenicity. Nat. Genet. 55, 1686–1695 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Wolf, Y. et al. UVB-induced tumor heterogeneity diminishes immune response in melanoma. Cell 179, 219–235.e21 (2019). Using a transplantable syngeneic mouse melanoma model, this seminal study is the first to experimentally demonstrate that intratumour heterogeneity limits the induction of antitumour immunity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Mroz, E. A. & Rocco, J. W. MATH, a novel measure of intratumor genetic heterogeneity, is high in poor-outcome classes of head and neck squamous cell carcinoma. Oral Oncol. 49, 211–215 (2013).

    Article  CAS  PubMed  Google Scholar 

  176. Patel, A. P. et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344, 1396–1401 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Zhang, J. et al. Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science 346, 256–259 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Jamal-Hanjani, M. et al. Tracking the evolution of non-small-cell lung cancer. N. Engl. J. Med. 376, 2109–2121 (2017). This study shows that intratumour heterogeneity is an adverse prognostic factor in lung cancer.

    Article  CAS  PubMed  Google Scholar 

  179. Gejman, R. S. et al. Rejection of immunogenic tumor clones is limited by clonal fraction. eLife 7, e41090 (2018). Using a reductionist approach, this study demonstrates that the clonal fraction contributes to determining the immunogenicity of tumour antigens in vivo.

    Article  PubMed  PubMed Central  Google Scholar 

  180. Morris, G. P. & Allen, P. M. How the TCR balances sensitivity and specificity for the recognition of self and pathogens. Nat. Immunol. 13, 121–128 (2012).

    Article  CAS  PubMed  Google Scholar 

  181. George, A. J. T., Stark, J. & Chan, C. Understanding specificity and sensitivity of T-cell recognition. Trends Immunol. 26, 653–659 (2005).

    Article  CAS  PubMed  Google Scholar 

  182. Gillis, S. & Roth, A. PyClone-VI: scalable inference of clonal population structures using whole genome data. BMC Bioinform. 21, 571 (2020).

    Article  Google Scholar 

  183. Sengupta, S. et al. Bayclone: Bayesian nonparametric inference of tumor subclones using NGS data. In Pacific Symposium on Biocomputing (PSB) 467–478 (PSB, 2015).

  184. Cmero, M. et al. Inferring structural variant cancer cell fraction. Nat. Commun. 11, 730 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Roth, A. et al. PyClone: statistical inference of clonal population structure in cancer. Nat. Methods 11, 396–398 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. van Dijk, E. et al. Chromosomal copy number heterogeneity predicts survival rates across cancers. Nat. Commun. 12, 3188 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  187. Battaglia, S. Neoantigen prediction from genomic and transcriptomic data. Methods Enzymol. 635, 267–281 (2020).

    Article  CAS  PubMed  Google Scholar 

  188. Rooney, M. S., Shukla, S. A., Wu, C. J., Getz, G. & Hacohen, N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160, 48–61 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Karn, T. et al. Association between genomic metrics and immune infiltration in triple-negative breast cancer. JAMA Oncol. 3, 1707–1711 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  190. Spranger, S. Tumor heterogeneity and tumor immunity: a chicken-and-egg problem. Trends Immunol. 37, 349–351 (2016).

    Article  CAS  PubMed  Google Scholar 

  191. Kurts, C. et al. CD8 T cell ignorance or tolerance to islet antigens depends on antigen dose. Proc. Natl Acad. Sci. USA 96, 12703–12707 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Ridge, J. P., Di Rosa, F. & Matzinger, P. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393, 474–478 (1998).

    Article  CAS  PubMed  Google Scholar 

  193. Mitchison, N. A. & O’Malley, C. Three-cell-type clusters of T cells with antigen-presenting cells best explain the epitope linkage and noncognate requirements of the in vivo cytolytic response. Eur. J. Immunol. 17, 1579–1583 (1987). This early study supports the model that antigen-presenting cells interact with various T cell populations to prime effective cytotoxic CD8+ T cell responses.

    Article  CAS  PubMed  Google Scholar 

  194. Lo, J. A. et al. Epitope spreading toward wild-type melanocyte-lineage antigens rescues suboptimal immune checkpoint blockade responses. Sci. Transl. Med. 13, eabd8636 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Burger, M. L. et al. Antigen dominance hierarchies shape TCF1+ progenitor CD8 T cell phenotypes in tumors. Cell 184, 4996–5014.e26 (2021). This study demonstrates that immunodominance hierarchies are established in cancer and lead to differential phenotypes and functions of dominant and subdominant T cell responses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Sercarz, E. E. et al. Dominance and crypticity of T cell antigenic determinants. Annu. Rev. Immunol. 11, 729–766 (1993).

    Article  CAS  PubMed  Google Scholar 

  198. Nguyen, T. H. O. et al. CD8+ T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope display high naive precursor frequency and TCR promiscuity. Immunity 54, 1066–1082.e5 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Song, I. et al. Broad TCR repertoire and diverse structural solutions for recognition of an immunodominant CD8+ T cell epitope. Nat. Struct. Mol. Biol. 24, 395–406 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Chen, G. et al. Sequence and structural analyses reveal distinct and highly diverse human CD8+ TCR repertoires to immunodominant viral antigens. Cell Rep. 19, 569–583 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Farrington, L. A., Smith, T. A., Grey, F., Hill, A. B. & Snyder, C. M. Competition for antigen at the level of the APC is a major determinant of immunodominance during memory inflation in murine cytomegalovirus infection. J. Immunol. 190, 3410–3416 (2013). This murine cytomegalovirus study shows that competition for antigen presentation by antigen-presenting cells determines immunodominance.

    Article  CAS  PubMed  Google Scholar 

  202. Jenkins, M. K. & Moon, J. J. The role of naive T cell precursor frequency and recruitment in dictating immune response magnitude. J. Immunol. 188, 4135–4140 (2012).

    Article  CAS  PubMed  Google Scholar 

  203. Kotturi, M. F. et al. Naive precursor frequencies and MHC binding rather than the degree of epitope diversity shape CD8+ T cell immunodominance. J. Immunol. 181, 2124–2133 (2008).

    Article  CAS  PubMed  Google Scholar 

  204. Obar, J. J., Khanna, K. M. & Lefrançois, L. Endogenous naive CD8+ T cell precursor frequency regulates primary and memory responses to infection. Immunity 28, 859–869 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Ge, Q., Bai, A., Jones, B., Eisen, H. N. & Chen, J. Competition for self-peptide-MHC complexes and cytokines between naive and memory CD8+ T cells expressing the same or different T cell receptors. Proc. Natl Acad. Sci. USA 101, 3041–3046 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Rappaport, A. R. et al. A shared neoantigen vaccine combined with immune checkpoint blockade for advanced metastatic solid tumors: phase 1 trial interim results. Nat. Med. 30, 1013–1022 (2024).

    Article  CAS  PubMed  Google Scholar 

  207. Turnbull, E. L. et al. Kinetics of expansion of epitope-specific T cell responses during primary HIV-1 infection. J. Immunol. 182, 7131–7145 (2009).

    Article  CAS  PubMed  Google Scholar 

  208. Shah, S. P. et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 486, 395–399 (2012).

    Article  CAS  PubMed  Google Scholar 

  209. Williams, M. J., Werner, B., Barnes, C. P., Graham, T. A. & Sottoriva, A. Identification of neutral tumor evolution across cancer types. Nat. Genet. 48, 238–244 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Galon, J. et al. Cancer classification using the Immunoscore: a worldwide task force. J. Transl. Med. 10, 205 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  211. Mao, Y. et al. The immune phenotypes and different immune escape mechanisms in colorectal cancer. Front. Immunol. 13, 968089 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Cristescu, R. et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362, eaar3593 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  213. Matsushita, H. et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482, 400–404 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. DuPage, M., Mazumdar, C., Schmidt, L. M., Cheung, A. F. & Jacks, T. Expression of tumour-specific antigens underlies cancer immunoediting. Nature 482, 405–409 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Sahin, U. et al. Human neoplasms elicit multiple specific immune responses in the autologous host. Proc. Natl Acad. Sci. USA 92, 11810–11813 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Kasiske, B. L., Snyder, J. J., Gilbertson, D. T. & Wang, C. Cancer after kidney transplantation in the United States. Am. J. Transpl. 4, 905–913 (2004).

    Article  Google Scholar 

  217. Sharkey, F. E. & Fogh, J. Incidence and pathological features of spontaneous tumors in athymic nude mice. Cancer Res. 39, 833–839 (1979).

    CAS  PubMed  Google Scholar 

  218. Ferrick, D. A., Sambhara, S. R., Chadwick, B. S., Miller, R. G. & Mak, T. W. The T-cell receptor repertoire is strikingly similar in older nude mice compared to normal adult mice. Thymus 13, 103–111 (1989).

    CAS  PubMed  Google Scholar 

  219. Engels, E. A. et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA 306, 1891–1901 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Van den Eynden, J., Jiménez-Sánchez, A., Miller, M. L. & Larsson, E. Lack of detectable neoantigen depletion signals in the untreated cancer genome. Nat. Genet. 51, 1741–1748 (2019). This bioinformatic study failed to detect neoantigen depletion in untreated cancers, possibly due to efficient immune evasion during early tumour evolution.

    Article  PubMed  PubMed Central  Google Scholar 

  221. Rogers, L. M., Olivier, A. K., Meyerholz, D. K. & Dupuy, A. J. Adaptive immunity does not strongly suppress spontaneous tumors in a Sleeping Beauty model of cancer. J. Immunol. 190, 4393–4399 (2013).

    Article  CAS  PubMed  Google Scholar 

  222. Martincorena, I. et al. Universal patterns of selection in cancer and somatic tissues. Cell 171, 1029–1041.e21 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Weghorn, D. & Sunyaev, S. Bayesian inference of negative and positive selection in human cancers. Nat. Genet. 49, 1785–1788 (2017).

    Article  CAS  PubMed  Google Scholar 

  224. Holmström, M. O. et al. High frequencies of circulating memory T cells specific for calreticulin exon 9 mutations in healthy individuals. Blood Cancer J. 9, 8 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  225. Robbins, P. F. et al. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat. Med. 19, 747–752 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Lu, Y. C. et al. Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions. Clin. Cancer Res. 20, 3401–3410 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. 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).

    Article  PubMed  Google Scholar 

  228. Guo, M., Peng, Y., Gao, A., Du, C. & Herman, J. G. Epigenetic heterogeneity in cancer. Biomark. Res. 7, 23 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  229. Stelmach, P. & Trumpp, A. Leukemic stem cells and therapy resistance in acute myeloid leukemia. Haematologica 108, 353–366 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Singh, S. K. et al. Identification of human brain tumour initiating cells. Nature 432, 396–401 (2004).

    Article  CAS  PubMed  Google Scholar 

  231. Taurin, S. & Alkhalifa, H. Breast cancers, mammary stem cells, and cancer stem cells, characteristics, and hypotheses. Neoplasia 22, 663–678 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Wainwright, E. N. & Scaffidi, P. Epigenetics and cancer stem cells: unleashing, hijacking, and restricting cellular plasticity. Trends Cancer 3, 372–386 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Jia, Q., Wang, A., Yuan, Y., Zhu, B. & Long, H. Heterogeneity of the tumor immune microenvironment and its clinical relevance. Exp. Hematol. Oncol. 11, 24 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Wu, F. et al. Single-cell profiling of tumor heterogeneity and the microenvironment in advanced non-small cell lung cancer. Nat. Commun. 12, 2540 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Nguyen, P. H. D. et al. Intratumoural immune heterogeneity as a hallmark of tumour evolution and progression in hepatocellular carcinoma. Nat. Commun. 12, 227 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Danenberg, E. et al. Breast tumor microenvironment structures are associated with genomic features and clinical outcome. Nat. Genet. 54, 660–669 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Yang, B. et al. Spatial heterogeneity of infiltrating T cells in high-grade serous ovarian cancer revealed by multi-omics analysis. Cell Rep. Med. 3, 100856 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Feng, L. et al. Heterogeneity of tumor-infiltrating lymphocytes ascribed to local immune status rather than neoantigens by multi-omics analysis of glioblastoma multiforme. Sci. Rep. 7, 6968 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  239. Al Bakir, M. et al. The evolution of non-small cell lung cancer metastases in TRACERx. Nature 616, 534–542 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Edeline, J., Houot, R., Marabelle, A. & Alcantara, M. CAR-T cells and BiTEs in solid tumors: challenges and perspectives. J. Hematol. Oncol. 14, 1–12 (2021).

    Article  Google Scholar 

  241. Robert, C. et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N. Engl. J. Med. 372, 30–39 (2015).

    Article  PubMed  Google Scholar 

  242. Rye, I. H. et al. Intratumor heterogeneity defines treatment-resistant HER2+ breast tumors. Mol. Oncol. 12, 1838–1855 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Holm, J. S. et al. Neoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma. Nat. Commun. 13, 1935 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Puig-Saus, C. et al. Neoantigen-targeted CD8+ T cell responses with PD-1 blockade therapy. Nature 615, 697–704 (2023). This study uses a large-scale screening approach to capture neoantigen-specific T cells and shows that effective immune checkpoint blockade therapy is associated with polyclonal CD8+ T cells that recognize a limited number of immunodominant epitopes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Reynisson, B., Alvarez, B., Paul, S., Peters, B. & Nielsen, M. NetMHCpan-4.1 and NetMHCIIpan-4.0: improved predictions of MHC antigen presentation by concurrent motif deconvolution and integration of MS MHC eluted ligand data. Nucleic Acids Res. 48, W449–w454 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Vita, R. et al. The Immune Epitope Database (IEDB): 2018 update. Nucleic Acids Res. 47, D339–D343 (2019).

    Article  CAS  PubMed  Google Scholar 

  247. Saxena, M., van der Burg, S. H., Melief, C. J. M. & Bhardwaj, N. Therapeutic cancer vaccines. Nat. Rev. Cancer 21, 360–378 (2021).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Stefani Spranger.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Immunology thanks Pramod Srivastava and the other, anonymous, reviewer(s) 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

Roerden, M., Spranger, S. Cancer immune evasion, immunoediting and intratumour heterogeneity. Nat Rev Immunol (2025). https://doi.org/10.1038/s41577-024-01111-8

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41577-024-01111-8

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing