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.

尽管癌症免疫疗法近年来取得了显著进展，但肿瘤发生早期免疫编辑的过程仍显得扑朔迷离。本研究中，我们运用一种数学模型，该模型基于癌症基因组图谱（TCGA）数据，旨在阐明个体突变和HLA等位基因对免疫编辑过程的贡献。研究发现，包括BRAF-V600E和KRAS-G12D在内的常见癌症突变预计无法与常见的HLA等位基因结合，因此在人类群体中表现为“免疫学沉默”。我们识别出在群体层面上HLA未呈现的蛋白质区域，这些区域与癌症中频繁突变的“热点”区域相吻合，以及其他在群体中广泛呈现但突变较少的蛋白质区域。此外，我们还发现9/29个常见的HLA等位基因对早期肿瘤发生突变的免疫编辑贡献不均。这些数据为常见驱动突变的免疫逃逸提供了洞见，并揭示了特定HLA基因型与癌症易感性关联的分子基础。