Rooney Michael S, Shukla Sachet A, Wu Catherine J, Getz Gad, Hacohen Nir
The Broad Institute, Cambridge, MA 02142, USA; Harvard/MIT Division of Health Sciences and Technology, Cambridge, MA 02141, USA.
The Broad Institute, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Cell. 2015 Jan 15;160(1-2):48-61. doi: 10.1016/j.cell.2014.12.033.
How the genomic landscape of a tumor shapes and is shaped by anti-tumor immunity has not been systematically explored. Using large-scale genomic data sets 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.
肿瘤的基因组格局如何塑造抗肿瘤免疫以及如何被抗肿瘤免疫塑造，尚未得到系统研究。利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征。预测的与MHC I类相关的新抗原数量与细胞溶解活性相关，在结直肠癌和其他肿瘤中低于预期，提示免疫介导的清除作用。我们鉴定出与细胞溶解活性呈正相关的反复突变基因，包括β2微球蛋白（B2M）、HLA-A、-B和-C以及半胱天冬酶8（CASP8），突出了抗原呈递缺失和外源性凋亡阻断作为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PDL1/2和ALOX12B/15B。因此，我们的遗传学发现为肿瘤中的免疫编辑提供了证据，并揭示了肿瘤内在抵抗细胞溶解活性的机制。
