Evolutionary pressure against MHC class II binding cancer mutations

• Rachel Marty Pyke ^[1] ; Wesley Kurt Thompson ^[1] ; Rany M. Salem ^[1]
  1. [1] University of California San Diego
• Localización: Cell, ISSN 0092-8674, Vol. 175, Nº. 2, 2018, págs. 416-428
• Idioma: inglés
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• Resumen

  • 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.