MHC II immunogenicity shapes the neoepitope landscape in human tumors.

Nature genetics 2023 Feb

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Despite advances in predicting physical peptide-major histocompatibility complex I (pMHC I) binding, it remains challenging to identify functionally immunogenic neoepitopes, especially for MHC II. By using the results of >36,000 immunogenicity assay, we developed a method to identify pMHC whose structural alignment facilitates T cell reaction. Our method predicted neoepitopes for MHC II and MHC I that were responsive to checkpoint blockade when applied to >1,200 samples of various tumor types. To investigate selection by spontaneous immunity at the single epitope level, we analyzed the frequency spectrum of >25 million mutations in >9,000 treatment-naive tumors with >100 immune phenotypes. MHC II immunogenicity specifically lowered variant frequencies in tumors under high immune pressure, particularly with high TCR clonality and MHC II expression. A similar trend was shown for MHC I neoepitopes, but only in particular tissue types. In summary, we report immune selection imposed by MHC II-restricted natural or therapeutic T cell reactivity. © 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

Citation

Jeong Yeon Kim, Hongui Cha, Kyeonghui Kim, Changhwan Sung, Jinhyeon An, Hyoeun Bang, Hyungjoo Kim, Jin Ok Yang, Suhwan Chang, Incheol Shin, Seung-Jae Noh, Inkyung Shin, Dae-Yeon Cho, Se-Hoon Lee, Jung Kyoon Choi. MHC II immunogenicity shapes the neoepitope landscape in human tumors. Nature genetics. 2023 Feb;55(2):221-231