Evolutionary Pressure against MHC Class II Binding Cancer Mutations

Rachel Marty Pyke; Wesley Kurt Thompson; Rany M Salem; Joan Font-Burgada; Maurizio Zanetti; Hannah Carter

doi:10.1016/j.cell.2018.08.048

Evolutionary Pressure against MHC Class II Binding Cancer Mutations

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

Authors

Rachel Marty Pyke¹, Wesley Kurt Thompson², Rany M Salem³, Joan Font-Burgada⁴, Maurizio Zanetti⁵, Hannah Carter⁶

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Age Factors
Animals
Antigens, Neoplasm / immunology
CD4-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / immunology
Evolution, Molecular
Histocompatibility Antigens Class I / genetics
Histocompatibility Antigens Class I / immunology
Histocompatibility Antigens Class II / genetics*
Histocompatibility Antigens Class II / immunology*
Humans
Immunotherapy / methods
Mutation / genetics
Neoplasms / genetics*

Substances

Antigens, Neoplasm
Histocompatibility Antigens Class I
Histocompatibility Antigens Class II

Abstract

Publication types

MeSH terms

Substances

Grants and funding