HLA Class I Analysis Provides Insight Into the Genetic and Epigenetic Background of Immune Evasion in Colorectal Cancer With High Microsatellite Instability
HLA Class I Analysis Provides Insight Into the Genetic and Epigenetic Background of Immune Evasion in Colorectal Cancer With High Microsatellite Instability
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HLA-I类分析揭示了具有高微卫星不稳定性的结直肠癌免疫逃避的遗传和表观遗传背景
DOI：
10.1053/j.gastro.2021.10.010
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发表时间：
2022-02-21
期刊：
影响因子：
29.4
通讯作者：
Mano, Hiroyuki
中科院分区：
文献类型：
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作者：
Kawazu, Masahito;Ueno, Toshihide;Mano, Hiroyuki
背景与目的：详细了解抗肿瘤免疫对于最佳的癌症免疫治疗是必不可少的。虽然在B2 M和HLA-ABC基因（编码抗原呈递所必需的分子）中的缺陷突变已在几项研究中报道，但这些缺陷对肿瘤免疫的影响尚未定量评估。方法：采用长片段测序仪分析114例微卫星不稳定性高的结直肠癌患者的HLA-ABC基因突变。结合全外显子组测序、转录组测序、DNA甲基化阵列和免疫组织化学数据进一步分析数据。结果：我们在57个肿瘤中检测到101个截短突变（50%），在21个肿瘤中检测到61个等位基因丢失（18%）。基于对微卫星不稳定性高的结直肠癌进行免疫学亚类分类的综合分析，我们确定了一种淋巴细胞浸润减少的肿瘤亚型，部分原因是在没有明显遗传改变的情况下HLA-ABC基因表达减少。这类肿瘤患者的生存时间短于其他类型的肿瘤患者。巧合的是，肿瘤突变负荷在亚型中最高，表明累积突变的免疫原性效应被减弱免疫反应性的突变抵消。各种遗传和表观遗传改变，包括RFX 5的移码突变和PSMB 8和HLA-A的启动子甲基化，集中在HLA-ABC基因表达的减少上。结论：我们详细的免疫基因组学分析提供的信息，将促进癌症免疫治疗的改进和发展。
BACKGROUND & AIMS: A detailed understanding of antitumor immunity is essential for optimal cancer immune therapy. Although defective mutations in the B2M and HLA-ABC genes, which encode molecules essential for antigen presentation, have been reported in several studies, the effects of these defects on tumor immunity have not been quantitatively evaluated. METHODS: Mutations in HLA-ABC genes were analyzed in 114 microsatellite instability-high colorectal cancers using a long-read sequencer. The data were further analyzed in combination with whole-exome sequencing, transcriptome sequencing, DNA methylation array, and immunohistochemistry data. RESULTS: We detected 101 truncating mutations in 57 tumors (50%) and loss of 61 alleles in 21 tumors (18%). Based on the integrated analysis that enabled the immunologic subclassification of microsatellite instability-high colorectal cancers, we identified a subtype of tumors in which lymphocyte infiltration was reduced, partly due to reduced expression of HLA-ABC genes in the absence of apparent genetic alterations. Survival time of patients with such tumors was shorter than in patients with other tumor types. Paradoxically, tumor mutation burden was highest in the subtype, suggesting that the immunogenic effect of accumulating mutations was counterbalanced by mutations that weakened immunoreactivity. Various genetic and epigenetic alterations, including frameshift mutations in RFX5 and promoter methylation of PSMB8 and HLA-A, converged on reduced expression of HLA-ABC genes. CONCLUSIONS: Our detailed immunogenomic analysis provides information that will facilitate the improvement and development of cancer immunotherapy.