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Cell. 2018 Oct 4;175(2):416-428.e13. doi: 10.1016/j.cell.2018.08.048. Epub 2018 Sep 20.

Evolutionary Pressure against MHC Class II Binding Cancer Mutations.

Author information

1
Department of Medicine, Division of Medical Genetics, University of California San Diego, La Jolla, CA 92093, USA; Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, CA 92093, USA.
2
Department of Family Medicine and Public Health, Division of Biostatistics & Bioinformatics, University of California San Diego, La Jolla, CA 92093, USA.
3
Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA 92093, USA.
4
Department of Pharmacology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Cancer Biology Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
5
Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA; The Laboratory of Immunology and Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
6
Department of Medicine, Division of Medical Genetics, University of California San Diego, La Jolla, CA 92093, USA; Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA; CIFAR, MaRS Centre, West Tower, 661 University Ave., Suite 505, Toronto, ON, Canada. Electronic address: hkcarter@ucsd.edu.

Abstract

The anti-cancer immune response against mutated peptides of potential immunological relevance (neoantigens) is primarily attributed to MHC-I-restricted cytotoxic CD8+ T cell responses. MHC-II-restricted CD4+ T cells also drive anti-tumor responses, but their relation to neoantigen selection and tumor evolution has not been systematically studied. Modeling the potential of an individual's MHC-II genotype to present 1,018 driver mutations in 5,942 tumors, we demonstrate that the MHC-II genotype constrains the mutational landscape during tumorigenesis in a manner complementary to MHC-I. Mutations poorly bound to MHC-II are positively selected during tumorigenesis, even more than mutations poorly bound to MHC-I. This emphasizes the importance of CD4+ T cells in anti-tumor immunity. In addition, we observed less inter-patient variation in mutation presentation for MHC-II than for MHC-I. These differences were reflected by age at diagnosis, which was correlated with presentation by MHC-I only. Collectively, our results emphasize the central role of MHC-II presentation in tumor evolution.

KEYWORDS:

MHC-II; T cells; cancer; driver mutations; immune editing; immunity; immunotherapy; tumor evolution

PMID:
30245014
DOI:
10.1016/j.cell.2018.08.048

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