Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade.
Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade.
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DOI：
10.1126/science.aaf1490
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发表时间：
2016-03-25
期刊：
影响因子：
--
通讯作者：
Swanton C
中科院分区：
文献类型：
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作者：
McGranahan N;Furness AJ;Rosenthal R;Ramskov S;Lyngaa R;Saini SK;Jamal-Hanjani M;Wilson GA;Birkbak NJ;Hiley CT;Watkins TB;Shafi S;Murugaesu N;Mitter R;Akarca AU;Linares J;Marafioti T;Henry JY;Van Allen EM;Miao D;Schilling B;Schadendorf D;Garraway LA;Makarov V;Rizvi NA;Snyder A;Hellmann MD;Merghoub T;Wolchok JD;Shukla SA;Wu CJ;Peggs KS;Chan TA;Hadrup SR;Quezada SA;Swanton C
随着肿瘤的生长，它们会发生突变，其中一些会产生新抗原，影响患者对免疫检查点抑制剂的反应。我们探讨了肿瘤内新抗原异质性（ITH）对抗肿瘤免疫的影响。通过对ITH和新抗原负荷的综合分析，我们证明了原发性肺腺癌中克隆性新抗原负荷与总生存率之间的关系。在早期非小细胞肺癌中鉴定了对克隆新抗原反应的CD 8+肿瘤浸润淋巴细胞，并表达高水平的PD-1。晚期NSCLC和黑色素瘤患者对PD-1和CTLA-4阻断的敏感性在富含克隆性新抗原的肿瘤中增强。在具有持久临床益处的患者中可检测到识别克隆新抗原的T细胞。细胞毒性化疗诱导的亚克隆新抗原，有助于增加突变负荷，在某些不良反应者中富集。这些数据表明，新抗原的异质性可能会影响免疫监视和支持靶向克隆新抗原的治疗发展。
As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8+ tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non–small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy–induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens.