| Literature DB >> 26940869 |
Nicholas McGranahan1, Andrew J S Furness2, Rachel Rosenthal3, Sofie Ramskov4, Rikke Lyngaa4, Sunil Kumar Saini4, Mariam Jamal-Hanjani3, Gareth A Wilson5, Nicolai J Birkbak5, Crispin T Hiley5, Thomas B K Watkins5, Seema Shafi3, Nirupa Murugaesu3, Richard Mitter6, Ayse U Akarca7, Joseph Linares7, Teresa Marafioti7, Jake Y Henry2, Eliezer M Van Allen8, Diana Miao9, Bastian Schilling10, Dirk Schadendorf10, Levi A Garraway8, Vladimir Makarov11, Naiyer A Rizvi12, Alexandra Snyder13, Matthew D Hellmann13, Taha Merghoub14, Jedd D Wolchok15, Sachet A Shukla9, Catherine J Wu16, Karl S Peggs2, Timothy A Chan11, Sine R Hadrup4, Sergio A Quezada17, Charles Swanton18.
Abstract
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.Entities:
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Year: 2016 PMID： 26940869 PMCID： PMC4984254 DOI： 10.1126/science.aaf1490
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728