Journal
CELL
Volume 175, Issue 2, Pages 416-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2018.08.048
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Funding
- NSF [2015205295]
- CIFAR
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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-H-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.
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