Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockadeMore about Open Access at the Crick
Authors listNicholas McGranahan Andrew JS Furness Rachel Rosenthal Sofie Ramskov Rikke Lyngaa Sunil Kumar Saini Mariam Jamal-Hanjani Gareth Wilson Nicolai Birkbak Crispin Hiley Tom Watkins Seema Shafi Nirupa Murugaesu Richard Mitter Ayse U Akarca Joseph Linares Teresa Marafioti Jake Y Henry Eliezer M Van Allen Diana Miao Bastian Schilling Dirk Schadendorf Levi A Garraway Vladimir Makarov Naiyer A Rizvi Alexandra Snyder Matthew D Hellmann Taha Merghoub Jedd D Wolchok Sachet A Shukla Catherine J Wu Karl S Peggs Timothy A Chan Sine R Hadrup Sergio A Quezada Charles Swanton
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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.
Issue number 6280