Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.
Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.
复制标题
癌症免疫学。突变景观决定了非小细胞肺癌中对PD-1阻滞的敏感性。
DOI：
10.1126/science.aaa1348
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发表时间：
2015-04-03
期刊：
影响因子：
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通讯作者：
Chan TA
中科院分区：
文献类型：
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作者：
Rizvi NA;Hellmann MD;Snyder A;Kvistborg P;Makarov V;Havel JJ;Lee W;Yuan J;Wong P;Ho TS;Miller ML;Rekhtman N;Moreira AL;Ibrahim F;Bruggeman C;Gasmi B;Zappasodi R;Maeda Y;Sander C;Garon EB;Merghoub T;Wolchok JD;Schumacher TN;Chan TA
免疫检查点抑制剂释放患者自身的T细胞杀死肿瘤，正在彻底改变癌症治疗。为了解开对这种疗法的反应的基因组决定因素，我们使用了pembrolizumab治疗的非小细胞肺癌的全外显子组测序，pembrolizumab是一种靶向程序性细胞死亡-1（PD-1）的抗体。在两个独立队列中，肿瘤中较高的非同义突变负荷与客观缓解改善、持久的临床获益和无进展生存期相关。疗效还与分子吸烟特征、较高的新抗原负荷和DNA修复途径突变相关;每个因素也与突变负荷相关。在一个应答者中，新抗原特异性CD 8 + T细胞应答促进肿瘤消退，表明抗PD-1治疗增强了新抗原特异性T细胞反应性。我们的研究结果表明，肺癌的基因组景观塑造了对抗PD-1治疗的反应。
Immune checkpoint inhibitors, which unleash a patient’s own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non–small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti–PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.