Molecular and genetic properties of tumors associated with local immune cytolytic activity.
Molecular and genetic properties of tumors associated with local immune cytolytic activity.
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DOI：
10.1016/j.cell.2014.12.033
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发表时间：
2015-01-15
期刊：
影响因子：
64.5
通讯作者：
Hacohen N
中科院分区：
文献类型：
--
作者：
Rooney MS;Shukla SA;Wu CJ;Getz G;Hacohen N
肿瘤的基因组景观是如何形成的，以及抗肿瘤免疫是如何形成的，还没有系统地研究过。使用实体组织肿瘤活检的大规模基因组数据集，我们量化了局部免疫浸润的细胞溶解活性，并确定了18种肿瘤类型的相关特性。预测的MHC I类相关新抗原的数量与细胞溶解活性相关，并且低于结肠直肠和其他肿瘤中的预期，表明免疫介导的消除。我们鉴定了与细胞溶解活性呈正相关的反复突变基因，包括β 2-微球蛋白（B2 M）、HLA-A、-B和-C以及半胱天冬酶8（CASP 8），强调了抗原呈递的丧失和外源性凋亡的阻断是抵抗细胞溶解活性的关键策略。基因扩增也与高细胞溶解活性相关，包括免疫抑制因子，如PDL 12和ALOX 12 B/15 B。因此，我们的遗传发现为肿瘤中的免疫编辑提供了证据，并揭示了肿瘤对细胞溶解活性的内在抗性机制。
How the genomic landscape of a tumor shapes and is shaped by anti-tumor immunity has not been systematically explored. Using large-scale genomic datasets of solid tissue tumor biopsies, we quantified the cytolytic activity of the local immune infiltrate and identified associated properties across 18 tumor types. The number of predicted MHC Class I-associated neoantigens was correlated with cytolytic activity and was lower than expected in colorectal and other tumors, suggesting immune-mediated elimination. We identified recurrently mutated genes that showed positive association with cytolytic activity, including beta-2-microglobulin (B2M), HLA-A, -B and -C and Caspase 8 (CASP8), highlighting loss of antigen presentation and blockade of extrinsic apoptosis as key strategies of resistance to cytolytic activity. Genetic amplifications were also associated with high cytolytic activity, including immunosuppressive factors such as PDL1/2 and ALOX12B/15B. Our genetic findings thus provide evidence for immunoediting in tumors and uncover mechanisms of tumor-intrinsic resistance to cytolytic activity.