"Evolutionary Pressure against MHC Class II Binding Cancer Mutations" published in Cell

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.

Hannah Carter
Hannah Carter
Principal Investigator

Dr. Carter is an Associate Professor in the UCSD Department of Medicine, Division of Medical Genetics. She received her Ph.D. in Biomedical Engineering from Johns Hopkins University and her M.Eng. in Electrical and Computer Engineering from the University of Louisville. She is an Azrieli Global Scholar, a Siebel Scholar and a recipient on a 2013 NIH Director’s Early Independence Award.

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