Diverse immune response of DNA damage repair-deficient tumors.
Diverse immune response of DNA damage repair-deficient tumors.
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DNA损伤修复缺陷肿瘤的不同免疫反应。
DOI：
10.1016/j.xcrm.2021.100276
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发表时间：
2021-05-18
期刊：
影响因子：
--
通讯作者：
Huang KL
中科院分区：
文献类型：
--
作者：
Qing T;Jun T;Lindblad KE;Lujambio A;Marczyk M;Pusztai L;Huang KL
具有DNA损伤修复（DDR）缺陷的肿瘤积累的基因组改变可能作为新抗原并增加对免疫检查点抑制剂的敏感性。然而，超过一半的ddr缺陷肿瘤对免疫治疗是难治性的，目前尚不清楚哪些突变可能促进哪些癌症类型的免疫原性。我们整合了代表32种癌症类型的10080种癌症的有害体细胞和种系突变以及DDR基因的甲基化数据，并评估了这些改变与肿瘤新抗原和免疫浸润的关系。我们的分析确定了DDR通路突变与更高的新抗原负荷、适应性免疫标记物和免疫检查点抑制剂治疗的动物模型和患者的生存结果相关。不同的免疫表型与不同类型的DDR缺乏相关，这取决于癌症类型背景。免疫反应相关的DDR缺陷的综合目录可以解释DDR缺陷癌症免疫治疗结果的变化，并促进免疫治疗基因组生物标志物的发展。肿瘤免疫原性与DNA损伤修复缺陷（DDR-ds）相关。DDR-d肿瘤的免疫原性因途径和癌症类型而异，具有高免疫浸润的DDR-d肿瘤与免疫治疗反应相关。Qing等人系统地比较了具有不同种系、体细胞和DNA损伤修复基因甲基化改变的肿瘤中的新抗原负荷、免疫浸润和免疫治疗反应。免疫原性受受影响的DDR通路和癌症类型的影响，特异性的DDR改变可能为免疫治疗提供更精确的生物标志物。
Tumors with DNA damage repair (DDR) deficiency accumulate genomic alterations that may serve as neoantigens and increase sensitivity to immune checkpoint inhibitor. However, over half of DDR-deficient tumors are refractory to immunotherapy, and it remains unclear which mutations may promote immunogenicity in which cancer types. We integrate deleterious somatic and germline mutations and methylation data of DDR genes in 10,080 cancers representing 32 cancer types and evaluate the associations of these alterations with tumor neoantigens and immune infiltrates. Our analyses identify DDR pathway mutations that are associated with higher neoantigen loads, adaptive immune markers, and survival outcomes of immune checkpoint inhibitor-treated animal models and patients. Different immune phenotypes are associated with distinct types of DDR deficiency, depending on the cancer type context. The comprehensive catalog of immune response-associated DDR deficiency may explain variations in immunotherapy outcomes across DDR-deficient cancers and facilitate the development of genomic biomarkers for immunotherapy. Tumor immunogenicity is associated with DNA damage repair deficiencies (DDR-ds) The immunogenicity of DDR alterations varies by pathways and cancer types DDR-d tumors with high immune infiltrates correlate with immunotherapy response Qing et al. systematically compare neoantigen loads, immune infiltrates, and immunotherapy responses in tumors harboring different germline, somatic, and methylation alterations of DNA damage repair genes. Immunogenicity is affected by the affected DDR pathway(s) and cancer types, and specific DDR alterations may provide more precise biomarkers for immunotherapy.
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影响因子：
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作者：
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