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Review
. 2016:130:25-74.
doi: 10.1016/bs.ai.2016.01.001. Epub 2016 Feb 10.

The Role of Neoantigens in Naturally Occurring and Therapeutically Induced Immune Responses to Cancer

Jeffrey P Ward  1 , Matthew M Gubin  1 , Robert D Schreiber  2
Affiliations
Review

The Role of Neoantigens in Naturally Occurring and Therapeutically Induced Immune Responses to Cancer

Jeffrey P Ward et al. Adv Immunol. 2016.

Abstract

Definitive experimental evidence from mouse cancer models and strong correlative clinical data gave rise to the Cancer Immunoediting concept that explains the dual host-protective and tumor-promoting actions of immunity on developing cancers. Tumor-specific neoantigens can serve as targets of spontaneously arising adaptive immunity to cancer and thereby determine the ultimate fate of developing tumors. Tumor-specific neoantigens can also function as optimal targets of cancer immunotherapy against established tumors. These antigens are derived from nonsynonymous mutations that occur during cellular transformation and, because they are foreign to the host genome, are not subject to central tolerance. In this review, we summarize the experimental evidence indicating that cancer neoantigens are the source of both spontaneously occurring and therapeutically induced immune responses against cancer. We also review the advances in genomics, bioinformatics, and cancer immunotherapy that have facilitated identification of neoantigens and have moved personalized cancer immunotherapies into clinical trials, with the promise of providing more specific, safer, more effective, and perhaps even more generalizable treatments to cancer patients than current immunotherapies.

Keywords: Cancer Immunoediting; Cancer immunotherapy; Checkpoint blockade immunotherapy; Neoantigens; Tumor-specific mutant antigens.

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Figures

Figure 1
Figure 1
Cancer Immunoediting is an extrinsic tumor-suppressor mechanism that engages after cellular transformation has occurred and intrinsic tumor-suppressor mechanisms have failed. In its most complex form, Cancer Immunoediting consists of three phases: Elimination, Equilibrium, and Escape. In the Elimination phase, innate and adaptive immunity work in concert to destroy emerging tumors before they become clinically apparent. This phase may represent the full extent of the process upon complete tumor elimination, whereby the host remains cancer free. If, however, a cancer cell variant resists elimination, it may then enter the Equilibrium phase, in which its outgrowth is immunologically constrained. Editing of tumor immunogenicity occurs in the Equilibrium phase. Equilibrium may curb outgrowth of occult cancers for the lifetime of the host. However, as a consequence of immune selection pressure, tumor cell variants may arise that are no longer recognized by adaptive immunity, become insensitive to immune effector mechanisms, and/or induce an immunosup-pressive tumor microenvironment. These tumor cells may then enter the Escape phase, in which their outgrowth is no longer impeded by immunity and thus manifest as clin-ically apparent cancer. Figure adapted from Vesely, M. D., Kershaw, M. H., Schreiber, R. D., & Smyth, M. J. (2011). Natural innate and adaptive immunity to cancer. Annual Review of Immunology, 29, 235–271. http://dx.doi.org/10.1146/annurev-immunol-031210–101324 and Schreiber, R. D., Old, L. J., & Smyth, M. J. (2011). Cancer immunoediting: Integrating immunity’s roles in cancer suppression and promotion. Science, 331(6024), 1565–1570. http://dx.doi.org/10.1126/science.1203486.
Figure 2
Figure 2
Genomics-and bioinformatics-based identification of mutant neoantigens. Tumor cells and normal tissue are subjected to whole exome and RNA-sequencing to identify expressed nonsynonymous somatic mutations. Corresponding mutant epi-topes are then analyzed in silico for MHC class I binding. Filters are then applied for anti-gen processing, whether the mutant epitope has a stronger predicted binding affinity than the corresponding wild-type peptide, and deprioritization of hypothetical proteins. Peptides corresponding to predicted epitopes are then synthesized and used to identify mutant neoantigen-specific T cells in freshly explanted TIL using MHC I multimer-based screens or functional assays (eg, cytokine release, ELISPOT, or intracellular cytokine staining) by peptide stimulation.
Figure 3
Figure 3
(A) Predicted MHC I binding affinity of filtered epitopes predicted by in silico analysis of missense mutations in the T3 tumor line. (B) Screening for specificities of CD8+ TIL from anti-PD-1-treated, T3 tumor-bearing mice using MHC I tetramers loaded with top predicted peptides. (C). IFN-γ and TNF-α induction in CD8+ TIL from anti-PD-1-treated, T3 tumor-bearing mice following culture with irradiated splenocytes pulsed with the top predicted peptides. Figure adapted from Gubin, M. M., Zhang, X., Schuster, H., Caron, E., Ward, J. P., Noguchi, T.,… Schreiber, R. D. (2014). Checkpoint block-ade cancer immunotherapy targets tumour-specific mutant antigens. Nature, 515(7528), 577–58. http://dx.doi.org/110.1038/nature13988.
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References

    1. Abelin JG, Trantham PD, Penny SA, Patterson AM, Ward ST, Hildebrand WH, … Hunt DF (2015). Complementary IMAC enrichment methods for HLA-associated phosphopeptide identification by mass spectrometry. Nature Protocols, 10(9), 1308–1318. 10.1038/nprot.2015.086. - DOI - PMC - PubMed
    1. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SAJR, Behjati S, Biankin AV, … Stratton MR (2013). Signatures of mutational processes in human cancer. Nature, 500(7463), 415–421. 10.1038/nature12477. - DOI - PMC - PubMed
    1. Altman JD, Moss PA, Goulder PJ, Barouch DH, McHeyzer-Williams MG, Bell JI, … Davis MM (1996). Phenotypic analysis of antigen-specific T lymphocytes. Science, 274(5284), 94–96. - PubMed
    1. Babbitt BP, Allen PM, Matsueda G, Haber E, & Unanue ER (1985). Binding of immunogenic peptides to Ia histocompatibility molecules. Nature, 317(6035), 359–361. - PubMed
    1. Bakker AB, Schreurs MW, de Boer AJ, Kawakami Y, Rosenberg SA, Adema GJ, & Figdor CG (1994). Melanocyte lineage-specific antigen gp100 is recognized by melanoma-derived tumor-infiltrating lymphocytes. Journal of Experimental Medicine, 179(3), 1005–1009. - PMC - PubMed

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