A Few Good Peptides: MHC Class I-based Cancer Immunosurveillance and Immunoevasion

Overview

Journal Nat Rev Immunol

Specialty Allergy & Immunology

Date 2020 Aug 22

PMID 32820267

Citations 120

Authors

Devin Dersh

Jaroslav Holly

Jonathan W Yewdell

Affiliations

Soon will be listed here.

Abstract

The remarkable success of immune checkpoint inhibitors demonstrates the potential of tumour-specific CD8 T cells to prevent and treat cancer. Although the number of lives saved by immunotherapy mounts, only a relatively small fraction of patients are cured. Here, we review two of the factors that limit the application of CD8 T cell immunotherapies: difficulties in identifying tumour-specific peptides presented by MHC class I molecules and the ability of tumour cells to impair antigen presentation as they evolve under T cell selection. We describe recent advances in understanding how peptides are generated from non-canonical translation of defective ribosomal products, relate this to the dysregulated translation that is a feature of carcinogenesis and propose dysregulated translation as an important new source of tumour-specific peptides. We discuss how the synthesis and function of components of the antigen-processing and presentation pathway, including the recently described immunoribosome, are manipulated by tumours for immunoevasion and point to common druggable targets that may enhance immunotherapy.

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References

Dunn G, Bruce A, Ikeda H, Old L, Schreiber R . Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002; 3(11):991-8. DOI: 10.1038/ni1102-991. View

Boon T, Van Pel A, De Plaen E, Chomez P, Lurquin C, Szikora J . Genes coding for T-cell-defined tum transplantation antigens: point mutations, antigenic peptides, and subgenic expression. Cold Spring Harb Symp Quant Biol. 1989; 54 Pt 1:587-96. DOI: 10.1101/sqb.1989.054.01.070. View

Sharma P, Allison J . The future of immune checkpoint therapy. Science. 2015; 348(6230):56-61. DOI: 10.1126/science.aaa8172. View

Linnemann C, van Buuren M, Bies L, Verdegaal E, Schotte R, Calis J . High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma. Nat Med. 2014; 21(1):81-5. DOI: 10.1038/nm.3773. View

Kreiter S, Vormehr M, van de Roemer N, Diken M, Lower M, Diekmann J . Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature. 2015; 520(7549):692-6. PMC: 4838069. DOI: 10.1038/nature14426. View

Alspach E, Lussier D, Miceli A, Kizhvatov I, DuPage M, Luoma A . MHC-II neoantigens shape tumour immunity and response to immunotherapy. Nature. 2019; 574(7780):696-701. PMC: 6858572. DOI: 10.1038/s41586-019-1671-8. View

Sledzinska A, Vila de Mucha M, Bergerhoff K, Hotblack A, Demane D, Ghorani E . Regulatory T Cells Restrain Interleukin-2- and Blimp-1-Dependent Acquisition of Cytotoxic Function by CD4 T Cells. Immunity. 2020; 52(1):151-166.e6. PMC: 7369640. DOI: 10.1016/j.immuni.2019.12.007. View

Schietinger A, Philip M, Liu R, Schreiber K, Schreiber H . Bystander killing of cancer requires the cooperation of CD4(+) and CD8(+) T cells during the effector phase. J Exp Med. 2010; 207(11):2469-77. PMC: 2964573. DOI: 10.1084/jem.20092450. View

Istrail S, Florea L, Halldorsson B, Kohlbacher O, Schwartz R, Yap V . Comparative immunopeptidomics of humans and their pathogens. Proc Natl Acad Sci U S A. 2004; 101(36):13268-72. PMC: 516558. DOI: 10.1073/pnas.0404740101. View

10.

Yewdell J . Immunology. Hide and seek in the peptidome. Science. 2003; 301(5638):1334-5. DOI: 10.1126/science.1089553. View

11.

Schubert U, Anton L, Gibbs J, Norbury C, Yewdell J, Bennink J . Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature. 2000; 404(6779):770-4. DOI: 10.1038/35008096. View

12.

Yewdell J, Anton L, Bennink J . Defective ribosomal products (DRiPs): a major source of antigenic peptides for MHC class I molecules?. J Immunol. 1996; 157(5):1823-6. View

13.

Anton L, Yewdell J . Translating DRiPs: MHC class I immunosurveillance of pathogens and tumors. J Leukoc Biol. 2014; 95(4):551-62. PMC: 3958739. DOI: 10.1189/jlb.1113599. View

14.

Wu T, Guan J, Handel A, Tscharke D, Sidney J, Sette A . Quantification of epitope abundance reveals the effect of direct and cross-presentation on influenza CTL responses. Nat Commun. 2019; 10(1):2846. PMC: 6599079. DOI: 10.1038/s41467-019-10661-8. View

15.

Croft N, Smith S, Wong Y, Tan C, Dudek N, Flesch I . Kinetics of antigen expression and epitope presentation during virus infection. PLoS Pathog. 2013; 9(1):e1003129. PMC: 3561264. DOI: 10.1371/journal.ppat.1003129. View

16.

Bourdetsky D, Schmelzer C, Admon A . The nature and extent of contributions by defective ribosome products to the HLA peptidome. Proc Natl Acad Sci U S A. 2014; 111(16):E1591-9. PMC: 4000780. DOI: 10.1073/pnas.1321902111. View

17.

McShane E, Sin C, Zauber H, Wells J, Donnelly N, Wang X . Kinetic Analysis of Protein Stability Reveals Age-Dependent Degradation. Cell. 2016; 167(3):803-815.e21. DOI: 10.1016/j.cell.2016.09.015. View

18.

Wei J, Zanker D, Di Carluccio A, Smelkinson M, Takeda K, Seedhom M . Varied Role of Ubiquitylation in Generating MHC Class I Peptide Ligands. J Immunol. 2017; 198(10):3835-3845. PMC: 5426817. DOI: 10.4049/jimmunol.1602122. View

19.

van Endert P . Post-proteasomal and proteasome-independent generation of MHC class I ligands. Cell Mol Life Sci. 2011; 68(9):1553-67. PMC: 11115176. DOI: 10.1007/s00018-011-0662-1. View

20.

Vinitsky A, Anton L, Snyder H, Orlowski M, Bennink J, Yewdell J . The generation of MHC class I-associated peptides is only partially inhibited by proteasome inhibitors: involvement of nonproteasomal cytosolic proteases in antigen processing?. J Immunol. 1997; 159(2):554-64. View