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

Nicholas McGranahan, Andrew J S Furness, Rachel Rosenthal, Sofie Ramskov Andersen, Rikke Birgitte Lyngaa, Sunil Kumar Saini, Mariam Jamal-Hanjani, Gareth A Wilson, Nicolai J. Birkbak, Crispin T Hiley, Thomas B K Watkins, Seema Shafi, Nirupa Murugaesu, Richard Mitter, Ayse U Akarca, Joseph Linares, Teresa Marafioti, Jake Y Henry, Eliezer M Van Allen, Diana MiaoBastian 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 Reker Hadrup, Sergio A Quezada, Charles Swanton

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    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.
    Original languageEnglish
    JournalScience
    Volume351
    Issue number6280
    Pages (from-to)1463-1469
    ISSN0036-8075
    DOIs
    Publication statusPublished - 2016

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