Table_3_Immunogenicity and Immune Silence in Human Cancer.XLSX

Despite recent advances in cancer immunotherapy, the process of immunoediting early in tumorigenesis remains obscure. Here, we employ a mathematical model that utilizes the Cancer Genome Atlas (TCGA) data to elucidate the contribution of individual mutations and HLA alleles to the immunoediting process. We find that common cancer mutations including BRAF-V600E and KRAS-G12D are predicted to bind none of the common HLA alleles, and are thus “immunogenically silent” in the human population. We identify regions of proteins that are not presented by HLA at a population scale, coinciding with frequently mutated hotspots in cancer, and other protein regions broadly presented across the population in which few mutations occur. We also find that 9/29 common HLA alleles contribute disproportionately to the immunoediting of early oncogenic mutations. These data provide insights into immune evasion of common driver mutations and a molecular basis for the association of particular HLA genotypes with cancer susceptibility.

尽管癌症免疫治疗近年来取得了诸多进展，但肿瘤发生早期的免疫编辑（immunoediting）过程仍未被完全阐明。本研究采用基于癌症基因组图谱（Cancer Genome Atlas, TCGA）数据的数学模型，旨在阐明单个突变与人类白细胞抗原（Human Leukocyte Antigen, HLA）等位基因在免疫编辑过程中的具体贡献。我们发现，包括BRAF-V600E与KRAS-G12D在内的常见癌症突变，经预测无法结合任何常见HLA等位基因，因此在人群中呈现‘免疫原性沉默（immunogenically silent）’状态。我们鉴定出两类蛋白质区域：一类在人群层面无法被HLA呈递，恰好对应癌症中的高频突变热点；另一类则在人群中广泛被HLA呈递，但该区域内极少发生突变。此外，我们发现29种常见HLA等位基因中有9种，对早期致癌突变的免疫编辑过程存在不成比例的显著贡献。本研究数据为常见驱动突变的免疫逃逸机制提供了新的见解，同时也为特定HLA基因型与癌症易感性的关联提供了分子层面的依据。