Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab.
Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab.
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DOI：
10.1016/j.cell.2017.09.028
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发表时间：
2017-11-02
期刊：
影响因子：
64.5
通讯作者：
Chan TA
中科院分区：
文献类型：
--
作者：
Riaz N;Havel JJ;Makarov V;Desrichard A;Urba WJ;Sims JS;Hodi FS;Martín-Algarra S;Mandal R;Sharfman WH;Bhatia S;Hwu WJ;Gajewski TF;Slingluff CL Jr;Chowell D;Kendall SM;Chang H;Shah R;Kuo F;Morris LGT;Sidhom JW;Schneck JP;Horak CE;Weinhold N;Chan TA
免疫检查点阻断在治疗期间调节肿瘤演变的机制尚不清楚。我们评估了来自68名晚期黑色素瘤患者的肿瘤基因组变化，这些患者在nivolumab开始之前和之后接受ipilimumab治疗或未接受ipilimumab治疗（CA 209 -038研究）。通过全外显子组、转录组和/或T细胞受体（TCR）测序来分析肿瘤。在应答患者中，突变和新抗原负荷较基线降低，治疗期间肿瘤内异质性分析表明肿瘤内存在差异性克隆进化，并且在治疗期间存在针对新抗原突变的推定选择。纳武利尤单抗治疗前和治疗期间的转录组分析显示，不同免疫细胞亚群的增加，特定转录网络的激活以及免疫检查点基因的上调在应答患者中更为明显。肿瘤内TCR库的时间变化揭示了在新抗原丢失的情况下T细胞克隆的扩增。本研究中的全面基因组分析数据提供了对nivolumab作用机制的深入了解。在黑色素瘤患者中，随着成功的检查点阻断治疗，突变负荷降低，这表明针对保护性突变新表位的选择可能是Nivolumab的关键作用机制
The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T-cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy. Transcriptome analyses before and during nivolumab therapy revealed increases in distinct immune cell subsets, activation of specific transcriptional networks, and upregulation of immune checkpoint genes that were more pronounced in patients with response. Temporal changes in intratumoral TCR repertoire revealed expansion of T-cell clones in the setting of neoantigen loss. Comprehensive genomic profiling data in this study provide insight into nivolumab mechanism of action. Mutation burden decreases with successful checkpoint blockade therapy in patients with melanoma, suggesting that selection against protective mutant neoepitopes may be a critical mechanism of action of Nivolumab
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影响因子：
56.9
作者：
Arstila, TP;Casrouge, A;Kourilsky, P
通讯作者：
Kourilsky, P
影响因子：
28.2
作者：
Chen PL;Roh W;Reuben A;Cooper ZA;Spencer CN;Prieto PA;Miller JP;Bassett RL;Gopalakrishnan V;Wani K;De Macedo MP;Austin-Breneman JL;Jiang H;Chang Q;Reddy SM;Chen WS;Tetzlaff MT;Broaddus RJ;Davies MA;Gershenwald JE;Haydu L;Lazar AJ;Patel SP;Hwu P;Hwu WJ;Diab A;Glitza IC;Woodman SE;Vence LM;Wistuba II;Amaria RN;Kwong LN;Prieto V;Davis RE;Ma W;Overwijk WW;Sharpe AH;Hu J;Futreal PA;Blando J;Sharma P;Allison JP;Chin L;Wargo JA
通讯作者：
Wargo JA
影响因子：
12.3
作者：
Fisher S;Barry A;Abreu J;Minie B;Nolan J;Delorey TM;Young G;Fennell TJ;Allen A;Ambrogio L;Berlin AM;Blumenstiel B;Cibulskis K;Friedrich D;Johnson R;Juhn F;Reilly B;Shammas R;Stalker J;Sykes SM;Thompson J;Walsh J;Zimmer A;Zwirko Z;Gabriel S;Nicol R;Nusbaum C
通讯作者：
Nusbaum C
推动CLL的突变及其在进展和复发中的演变。
影响因子：
64.8
作者：
Landau DA;Tausch E;Taylor-Weiner AN;Stewart C;Reiter JG;Bahlo J;Kluth S;Bozic I;Lawrence M;Böttcher S;Carter SL;Cibulskis K;Mertens D;Sougnez CL;Rosenberg M;Hess JM;Edelmann J;Kless S;Kneba M;Ritgen M;Fink A;Fischer K;Gabriel S;Lander ES;Nowak MA;Döhner H;Hallek M;Neuberg D;Getz G;Stilgenbauer S;Wu CJ
通讯作者：
Wu CJ
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