Table_4_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.

尽管近年来癌症免疫治疗取得了显著进展，但在肿瘤发生早期免疫编辑的过程仍然晦涩不明。在本研究中，我们运用数学模型，利用癌症基因组图谱（TCGA）数据，阐释了单个突变和HLA等位基因对免疫编辑过程的贡献。我们发现，包括BRAF-V600E和KRAS-G12D在内的常见癌症突变预计与所有常见的HLA等位基因均无结合，因此在人类群体中表现为“免疫原性沉默”。我们确定了在群体层面上未由HLA呈递的蛋白质区域，这些区域与癌症中频繁突变的“热点”相吻合，以及其他在群体中广泛呈递但突变很少发生的蛋白质区域。此外，我们还发现，在29个常见HLA等位基因中，有9个对早期致癌突变的免疫编辑具有不成比例的贡献。这些数据为常见驱动突变的免疫逃逸提供了见解，并为特定HLA基因型与癌症易感性之间的关联提供了分子基础。