Department of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea.
Penta Medix Co., Ltd., Seongnam-si, Republic of Korea.
Nat Genet. 2023 Feb;55(2):221-231. doi: 10.1038/s41588-022-01273-y. Epub 2023 Jan 9.
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.
尽管在预测物理肽-主要组织相容性复合体 I (pMHC I) 结合方面取得了进展，但识别功能免疫原性的新表位仍然具有挑战性，特别是对于 MHC II 而言。通过使用超过 36000 次免疫原性测定的结果，我们开发了一种方法来识别结构上有利于 T 细胞反应的 pMHC。我们的方法预测了针对 MHC II 和 MHC I 的新表位，当应用于超过 1200 个各种肿瘤类型的样本时，这些新表位对检查点阻断有反应。为了在单个表位水平上研究自发免疫的选择，我们分析了 >9000 个未经治疗的肿瘤中 >2500 万个突变的频率谱，这些肿瘤具有 >100 种免疫表型。MHC II 的免疫原性特异性降低了高免疫压力下肿瘤中的变异频率，尤其是在 TCR 克隆性和 MHC II 表达较高的情况下。MHC I 新表位也表现出类似的趋势，但仅在特定组织类型中。总之，我们报告了 MHC II 限制的天然或治疗性 T 细胞反应所施加的免疫选择。
