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The determinants of tumour immunogenicity

Abstract

Many standard and targeted therapies, as well as radiotherapy, have been shown to induce an anti-tumour immune response, and immunotherapies rely on modulating the host immune system to induce an anti-tumour immune response. However, the immune response to such therapies is often reliant on the immunogenicity of a tumour. Tumour immunogenicity varies greatly between cancers of the same type in different individuals and between different types of cancer. So, what do we know about tumour immunogenicity and how might we therapeutically improve tumour immunogenicity? We asked four leading cancer immunologists around the world for their opinions on this important issue.

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References

  1. Willimsky, G. et al. Immunogenicity of premalignant lesions is the primary cause of general cytotoxic T lymphocyte unresponsiveness. J. Exp. Med. 205, 1687–1700 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Seung, L. P., Seung, S. K. & Schreiber, H. Antigenic cancer cells that escape immune destruction are stimulated by host cells. Cancer Res. 55, 5094–5100 (1995).

    CAS  PubMed  Google Scholar 

  3. Preiss, S., Kammertoens, T., Lampert, C., Willimsky, G. & Blankenstein, T. Tumor-induced antibodies resemble the response to tissue damage. Int. J. Cancer 115, 456–462 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Lennerz V. et al. The response of autologous T cells to a human melanoma is dominated by mutated neoantigens. Proc. Natl Acad. Sci. USA 102, 16013–16018 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Boon, T., Cerottini, J.-C., Van den Eynde, B., van der Bruggen, P. & Van Pel, A. Tumor antigens recognized by T lymphocytes. Annu. Rev. Immunol. 12, 337–365 (1994).

    Article  CAS  PubMed  Google Scholar 

  6. 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).

    Article  CAS  PubMed  Google Scholar 

  7. Gotter, J., Brors, B., Hergenhahn, M. & Kyewski, B. Medullary epithelial cells of the human thymus express a highly diverse selection of tissue-specific genes colocalized in chromosomal clusters. J. Exp. Med. 199, 155–166 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kloor, M., Michel, S. & von Knebel Doeberitz, M. Immune evasion of microsatellite unstable colorectal cancers. Int. J. Cancer 127, 1001–1010 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Casares, N. et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J. Exp. Med. 202, 1691–1701 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fridman, W. H. et al. Prognostic and predictive impact of intra- and peritumoral immune infiltrates. Cancer Res. 71, 5601–5605 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Perez-Diez, A. et al. CD4 cells can be more efficient at tumor rejection than CD8 cells. Blood 109, 5346–5354 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zitvogel, L., Tesniere, A. & Kroemer, G. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nature Rev. Immunol. 6, 715–727 (2006).

    Article  CAS  Google Scholar 

  14. Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumor escape. Nature Immunol. 3, 991–998 (2002).

    Article  CAS  Google Scholar 

  15. Klebanoff, C. A., Gattinoni, L. & Restifo, N. P. CD8+ T-cell memory in tumor immunology and immunotherapy. Immunol. Rev. 211, 214–224 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tredan, O., Galmarini, C. M., Patel, K. & Tannock, I. F. Drug resistance and the solid tumor microenvironment. J. Natl Cancer Inst. 99, 1441–1454 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Hamzah, J. et al. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453, 410–414 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Buckanovich, R. J. et al. Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nature Med. 14, 28–36 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Burnet, F. M. Immunological factors in the process of carcino-genesis. Br. Med. Bull. 20L, 154–158 (1964).

    Article  Google Scholar 

  20. Thomas, L. On immunosurveillance in human cancer. Yale J. Biol. Med. 55, 329–333 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Langman, R. E., Cohn, M. A minimal model for the self-non-self discrimination: a return to the basics. Semin. Immunol. 12, 189–195 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Dunn, G. P., Old, L. J. & Schreiber, R. D. The immunobiology of Cancer Immunosurveillance and Immunoediting. Immunity 21, 137–148 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Pradeu, T. & Carosella, E. D. On the definition of a criterion of immunogenicity. Proc. Natl Acad. Sci. USA 103, 17858–17861 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Drake, C. G., Jaffee, E. M. & Pardoll, D. M. Mechanisms of immune evasion by tumors. Adv. Immunol. 90, 51–81 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Laheru, D. A. & Jaffee, E. M. Immunotherapy for pancreatic cancer – science driving clinical practice. Nature Rev. Cancer 5, 459–467 (2005).

    Article  CAS  Google Scholar 

  26. Cohn, M. The immune system: a weapon of mass destruction invented by evolution to even the odds during the war of the DNAs. Immunol. Rev. 185, 24–38 (1992).

    Article  Google Scholar 

  27. Khong, H. T. & Restifo, N. P. Natural selection of tumor variants in the generation of “tumor escape” variants. Nature Immunol. 3, 999–1005 (2002).

    Article  CAS  Google Scholar 

  28. Klein, G. & Klein, E. Immune surveillance against virus-induced tumors and nonrejectability of spontaneous tumors: contrasting consequences of host versus tumor evolution. Proc. Natl Acad. Sci. USA 74, 2121–2125 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Shankaran, V. et al. IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–1111 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Qin, Z. & Blankenstein, T. A cancer immunosurveillance controversy. Nature Immunol. 5, 3–4 (2004).

    Article  CAS  Google Scholar 

  31. Kammertoens, T., Qin, Z., Briesemeister, D., Bendelac, A. & Blankenstein, T. Methylcholanthrene-induced carcinogenesis is promoted by B-cells and IL-4 but there is no evidence for a role of T/NKT-cells and their effector molecules (Fas-ligand, TNF-α, perforin). Int. J. Cancer 31 Jan 2012 (doi:10.1002/ijc.27411).

    Article  CAS  PubMed  Google Scholar 

  32. Pantel, K. & Uhr, J. W. Controversies in clinical cancer dormancy. Proc. Natl Acad. Sci. USA 108, 12396–12400 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Garrido, F., Cabrera, T. & Aptsiauri, N. “Hard” and “soft” lesions underlying the HLA class I alterations in cancer cells: implications for immunotherapy. Int. J. Cancer 127, 249–256 (2010).

    CAS  PubMed  Google Scholar 

  34. Gajewski, T. F. et al. Immune resistance orchestrated by the tumor microenvironment. Immunol. Rev. 213, 131–145 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Uyttenhove, C. et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nature Med. 9, 1269–1274 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Opitz, C. A. et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197–203 (2011).

    Article  CAS  PubMed  Google Scholar 

  37. Pilotte, L. et al. Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proc. Natl Acad. Sci. USA 109, 2497–2502 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Demotte, N. et al. A galectin-3 ligand corrects the impaired function of human CD4 and CD8 tumor-infiltrating lymphocytes and favors tumor rejection in mice. Cancer Res. 70, 7476–7488 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Med. 10, 942–949 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Gobert, M. et al. Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res. 69, 2000–2009 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nature Rev. Immunol. 9, 162–174 (2009).

    Article  CAS  Google Scholar 

  42. Boon, T., Coulie, P. G., Van den Eynde, B. & van der Bruggen, P. Human T cell responses against melanoma. Annu. Rev. Immunol. 24, 175–208 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Corbière, V. et al. Antigen spreading contributes to MAGE vaccination-induced regression of melanoma metastases. Cancer Res. 71, 1253–1262 (2011).

    Article  PubMed  Google Scholar 

  44. Willimsky, G. & Blankenstein, T. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature 437, 141–146 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Neefjes, J., Jongsma, M. L., Paul, P. & Bakke, O. Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nature Rev. Immunol. 11, 823–836 (2011).

    Article  CAS  Google Scholar 

  46. Rezvani, K. & de lavallade, H. Vaccination strategies for lymphomas and leukemias: recent progress. Drugs 71, 1659–1674 (2011).

    Article  CAS  PubMed  Google Scholar 

  47. Scanlan, M. J., Gure, A. O., Jungbluth, A. A., Old, L. J. & Chen, Y. T. Cancer/testis antigens: an expanding family of targets for cancer immunotherapy. Immunol. Rev. 188, 22–32 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Zheng, L. et al. Tyrosine 23 phosphorylation-dependent cell-surface localization of annexin A2 is required for invasion and metastases of pancreatic cancer. PLoS ONE 6, e19390 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lampen, M. H. & van Hall, T. Strategies to counteract MHC-1 defects in tumors. Curr. Opin. Immunol. 23, 293–298 (2011).

    Article  CAS  PubMed  Google Scholar 

  50. Topalian, S. L., Weiner, G. J. & Pardoll, D. M. Cancer immunotherapy comes of age. J. Clin. Oncol. 29, 4828–4836 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Schietinger, A., Delrow, J. J., Basom, R. S., Blattman, J. N. & Greenberg, P. D. Rescued tolerant CD8 T cells are preprogrammed to reestablish the tolerant state. Science 335, 723–727 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ganss, R. & Hanahan, D. Tumor microenvironment can restrict the effectiveness of activated antitumor lymphocytes. Cancer Res. 58, 4673–4681 (1998).

    CAS  PubMed  Google Scholar 

  53. Huber, M. L., Haynes, L., Parker, C. & Iversen, P. Interdisciplinary critique of Sipuleucel-T as immunotherapy in castration-resistant prostate cancer. J. Natl Cancer Inst. 104, 1–7 (2012).

    Article  Google Scholar 

  54. Horowitz, M. M. et al. Graft-versus-Leukemia reactions after bone marrow transplantation. Blood 75, 555–562 (1990).

    CAS  PubMed  Google Scholar 

  55. Wilde, S. et al. Dendritic cells pulsed with RNA encoding allogenic MHC and antigen induce T cells with superior anti-tumor activity and higher functional TCR avidity. Blood 114, 2131–2139 (2009).

    Article  CAS  PubMed  Google Scholar 

  56. Li, L.-P. et al. Transgenic mice with a diverse human T-cell antigen receptor repertoire. Nature Med. 16, 1029–1034 (2010).

    Article  CAS  PubMed  Google Scholar 

  57. Schumacher, T. N. T-cell-receptor gene therapy. Natur. Rev. Immunol. 2, 512–519 (2002).

    Article  CAS  Google Scholar 

  58. Offringa, R. Antigen choice in adoptive T-cell therapy of cancer. Curr. Opin. Immunol. 21, 190–199 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Nair, S. et al. Synergy between tumor immunotherapy and antiangiogenic therapy. Blood 102, 964–971 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Niethammer, A. G. et al. A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth. Nature Med. 8, 1369–1375 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Pastor, F., Kolonias, D., Giangrande, P. H. & Gilboa, E. Induction of tumour immunity by targeted inhibition of nonsense-mediated mRNA decay. Nature 465, 227–230 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Pastor, F., Kolonias, D., McNamara, J. O. & Gilboa, E. Targeting 4–1BB costimulation to disseminated tumor lesions with bi-specific oligonucleotide aptamers. Mol. Ther. 19, 1878–1886 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Gattinoni, L. et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nature Med. 15, 808–813 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Olive, K. P. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457–1461 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Sugahara, K. N. et al. Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science 328, 1031–1035 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ma, Y. et al. Chemotherapy and radiotherapy: cryptic anticancer vaccines. Sem. Immunol. 22, 113–124 (2010).

    Article  Google Scholar 

  67. Kantoff, P. W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411–422 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. 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 

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Acknowledgements

L.M.J. wishes to thank The Skip Viragh Pancreatic Cancer Center.

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Correspondence to Thomas Blankenstein, Pierre G. Coulie, Eli Gilboa or Elizabeth M. Jaffee.

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Related links

Glossary

Adaptive immune responses

Responses mediated by antigen-specific lymphocytes and antibodies, they are highly antigen-specific and include the development of immunological memory.

Allogeneic

From different individuals of the same species.

Anergic

A state in which T cells are unresponsive and cannot be activated by antigen.

Antigenicity

The ability to be recognized by the immune system by binding to T and B cell receptors, although this might not result in overt responses.

Autochthonous

Formed from endogenous tissue in the correct anatomical location.

Cancer-germline genes

Embryonic genes that are normally only expressed in male germline cells that become expressed in cancer. Can also be described as cancer-testis genes.

Desmoplasia

The growth of fibrous or connective tissue.

DNA mismatch repair

DNA repair mechanism that corrects mispaired nucleotides that originate during DNA replication and recombination.

Graft-versus-host disease

Inflammatory and tissue-destructive immune reactions that result from the attack on host tissues by infused allogeneic lymphocytes.

Graft-versus-leukaemia

Following allogeneic transplantation of bone marrow or blood stem cells, donor T cells may recognize peptides on leukaemia cells that result in beneficial immune attack.

Human leukocyte antigen

Cell-surface molecules that are encoded by the major histocompatibility complex. These molecules present antigenic peptides to T cells. HLA class I molecules present antigen to CD8+ T lymphocytes, and HLA class II molecules present antigen to CD4+ T lymphocytes.

Immunoediting

Describes the complex relationship between a developing tumour that is under constant pressure from the host immune system. Cancer immunoediting consists of three phases: elimination (that is, cancer immunosurveillance), equilibrium and escape.

Lymphopenia

Reduced numbers of lymphocytes, commonly following radiotherapy or chemotherapy.

Minor histocompatibility

Polymorphic peptides derived from normal cellular proteins that can be recognized in the context of major histocompatibility complex molecules. Immune responses against these polymorphic antigens can result in graft-versus-host reactions, graft rejection or beneficial anti-tumour responses.

Regulatory T (TReg) cells

A T cell subpopulation that suppresses the activation of other T cells and that maintains immune system homeostasis and peripheral tolerance to self-antigens.

Syngeneic

Genetically identical.

Tolerance

The process that ensures that repertoires of B cells and T cells are biased against self-reactivity, which reduces the likelihood of autoimmunity.

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Blankenstein, T., Coulie, P., Gilboa, E. et al. The determinants of tumour immunogenicity. Nat Rev Cancer 12, 307–313 (2012). https://doi.org/10.1038/nrc3246

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