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Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade.


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.

SUBMITTER: McGranahan N 

PROVIDER: S-EPMC4984254 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade.

McGranahan Nicholas N   Furness Andrew J S AJ   Rosenthal Rachel R   Ramskov Sofie S   Lyngaa Rikke R   Saini Sunil Kumar SK   Jamal-Hanjani Mariam M   Wilson Gareth A GA   Birkbak Nicolai J NJ   Hiley Crispin T CT   Watkins Thomas B K TB   Shafi Seema S   Murugaesu Nirupa N   Mitter Richard R   Akarca Ayse U AU   Linares Joseph J   Marafioti Teresa T   Henry Jake Y JY   Van Allen Eliezer M EM   Miao Diana D   Schilling Bastian B   Schadendorf Dirk D   Garraway Levi A LA   Makarov Vladimir V   Rizvi Naiyer A NA   Snyder Alexandra A   Hellmann Matthew D MD   Merghoub Taha T   Wolchok Jedd D JD   Shukla Sachet A SA   Wu Catherine J CJ   Peggs Karl S KS   Chan Timothy A TA   Hadrup Sine R SR   Quezada Sergio A SA   Swanton Charles C  

Science (New York, N.Y.) 20160303 6280


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 e  ...[more]

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