Rizvi Naiyer A, Hellmann Matthew D, Snyder Alexandra, Kvistborg Pia, Makarov Vladimir, Havel Jonathan J, Lee William, Yuan Jianda, Wong Phillip, Ho Teresa S, Miller Martin L, Rekhtman Natasha, Moreira Andre L, Ibrahim Fawzia, Bruggeman Cameron, Gasmi Billel, Zappasodi Roberta, Maeda Yuka, Sander Chris, Garon Edward B, Merghoub Taha, Wolchok Jedd D, Schumacher Ton N, Chan Timothy A
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY, 10065, USA.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY, 10065, USA. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Science. 2015 Apr 3;348(6230):124-8. doi: 10.1126/science.aaa1348. Epub 2015 Mar 12.
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.
免疫检查点抑制剂能够释放患者自身的T细胞来杀死肿瘤，正在彻底改变癌症治疗方式。为了揭示对这种疗法反应的基因组决定因素，我们对接受派姆单抗（一种靶向程序性细胞死亡蛋白1（PD-1）的抗体）治疗的非小细胞肺癌进行了全外显子测序。在两个独立队列中，肿瘤中较高的非同义突变负担与客观缓解改善、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、较高的新抗原负担和DNA修复途径突变相关；每个因素也与突变负担相关。在一名缓解者中，新抗原特异性CD8 + T细胞反应与肿瘤消退平行，表明抗PD-1疗法增强了新抗原特异性T细胞反应性。我们的结果表明，肺癌的基因组格局塑造了对抗PD-1疗法的反应。
