Association of clock-like mutational signature with immune checkpoint inhibitor outcome in patients with melanoma and NSCLC.
Association of clock-like mutational signature with immune checkpoint inhibitor outcome in patients with melanoma and NSCLC.
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DOI：
10.1016/j.omtn.2020.10.033
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发表时间：
2021-03-05
期刊：
影响因子：
--
通讯作者：
Chen H
中科院分区：
文献类型：
--
作者：
Chong W;Wang Z;Shang L;Jia S;Liu J;Fang Z;Du F;Wu H;Liu Y;Chen Y;Chen H
免疫检查点抑制剂（ICI）治疗在黑色素瘤和非小细胞肺癌（NSCLC）中取得了显著的临床疗效。肿瘤突变特征是在整个肿瘤发生和异质性过程中起作用的内源性和外源性因素的指纹；然而，它们与ici处理样本中免疫反应的关系尚不清楚。在这里，我们利用基于全外显子组测序（WES）的突变谱，结合来自黑色素瘤和非小细胞肺癌数据集的临床病理特征，来研究肿瘤基因组特征是否有助于ICI治疗的临床获益。从靶向下一代测序（NGS）测定（MSK-IMPACT面板）获得的突变数据也被用于进一步证实。在WES和靶向NGS免疫治疗队列中，以NpCpG三核苷酸的C b> T突变富集为特征的突变特征（称为年龄相关的时钟样加工）被确定与较差的预后和较低的肿瘤突变负荷（TML）相关。我们还分析了基因转录组谱，并确定了免疫调节相关的基因通路，这些基因通路在具有不同时钟样特征分组的样品中显着改变。白细胞亚群分析进一步显示，时钟样特征与细胞毒性细胞浸润减少和调节性T细胞升高有关。总的来说，我们的工作重新说明了与年龄相关的时钟样特征与较差的预后和较低的免疫活性相关，这为基于基因组亚型将患者分层为最佳免疫治疗方案提供了机会。肿瘤突变特征是在整个肿瘤发生和异质性过程中起作用的内源性和外源性因素的指纹。Chong等人发现，钟样突变特征与突变负荷和对免疫检查点抑制剂（ICI）治疗的耐药性有关，这为基于基因组亚型将患者分层为最佳免疫治疗方案提供了机会。
Immune checkpoint inhibitor (ICI) therapy has achieved remarkable clinical benefit in melanoma and non-small cell lung cancer (NSCLC). Tumor mutational signatures are the fingerprints of endogenous and exogenous factors that have acted throughout tumorigenesis and heterogeneity; however, their association with immune response in ICI-treated samples remains unclear. Here, we leveraged whole-exome sequencing (WES)-based mutational profiles combined with clinicopathologic characteristics from melanoma and NSCLC datasets to examine whether tumor genomic features contribute to clinical benefit of ICI treatment. Mutational data acquired from targeted next-generation sequencing (NGS) assays (MSK-IMPACT panels) were also employed for further corroboration. A mutational signature (known as age-related clock-like processing) characterized by enrichment of C>T mutations at NpCpG trinucleotides were identified to be associated with a worse prognosis and lower tumor mutation load (TML) in both WES and targeted NGS immunotherapy cohorts. We also analyzed gene transcriptomic profiles and identified immune regulation-related gene pathways that were significantly altered in samples with different clock-like signature grouping. Leucocyte subset analysis further revealed that clock-like signature was associated with the reduction of cytotoxic cell infiltration and elevation of regulatory T cells. Overall, our work re-annotated that the age-related clock-like signature was associated with worse prognosis and lower immune activity, offering opportunities to stratify patients into optimal immunotherapy plans based on genomic subtyping. Tumor mutational signatures are the fingerprints of endogenous and exogenous factors that have acted throughout tumorigenesis and heterogeneity. Chong et al. revealed that the clock-like mutational signature was associated with mutation load and resistance to immune checkpoint inhibitor (ICI) treatment, offering opportunities to stratify patients into optimal immunotherapy plans based on genomic subtyping.
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影响因子：
10.3
作者：
Desrichard, Alexis;Kuo, Fengshen;Morris, Luc G. T.
通讯作者：
Morris, Luc G. T.
影响因子：
--
作者：
Lee B;Lee T;Lee SH;Choi YL;Han J
通讯作者：
Han J
影响因子：
64.8
作者：
Ghandi, Mahmoud;Huang, Franklin W.;Sellers, William R.
通讯作者：
Sellers, William R.
DOI：
10.1126/science.aar3593
发表时间：
2018-10-12
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cristescu R;Mogg R;Ayers M;Albright A;Murphy E;Yearley J;Sher X;Liu XQ;Lu H;Nebozhyn M;Zhang C;Lunceford JK;Joe A;Cheng J;Webber AL;Ibrahim N;Plimack ER;Ott PA;Seiwert TY;Ribas A;McClanahan TK;Tomassini JE;Loboda A;Kaufman D
通讯作者：
Kaufman D
影响因子：
64.5
作者：
Hugo W;Zaretsky JM;Sun L;Song C;Moreno BH;Hu-Lieskovan S;Berent-Maoz B;Pang J;Chmielowski B;Cherry G;Seja E;Lomeli S;Kong X;Kelley MC;Sosman JA;Johnson DB;Ribas A;Lo RS
通讯作者：
Lo RS