Статья

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

Nicholas McGranahanCancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UKAndrew J.S. FurnessCancer Immunology Unit, UCL Cancer Institute, UCL, London WC1E 6BT, UKRachel RosenthalCancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UKSofie RamskovSection for Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark, 1970 Frederiksberg C, DenmarkRikke LyngaaSection for Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark, 1970 Frederiksberg C, DenmarkSunil Kumar SainiSection for Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark, 1970 Frederiksberg C, DenmarkMariam Jamal‐HanjaniCancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UKGareth A. WilsonCancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UKNicolai J. BirkbakCancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UKCrispin T. HileyCancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UKThomas B.K. WatkinsCancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UKSeema ShafiCancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UKNirupa MurugaesuCancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UKRichard MitterThe Francis Crick Institute, London WC2A 3LY, UKAyse U. AkarcaCancer Immunology Unit, UCL Cancer Institute, UCL, London WC1E 6BT, UKJoseph LinaresCancer Immunology Unit, UCL Cancer Institute, UCL, London WC1E 6BT, UKTeresa MarafiotiCancer Immunology Unit, UCL Cancer Institute, UCL, London WC1E 6BT, UKJake Y. HenryCancer Immunology Unit, UCL Cancer Institute, UCL, London WC1E 6BT, UKEliezer M. Van AllenBroad Institute of MIT and Harvard, Cambridge, MA 02142, USADiana MiaoBroad Institute of MIT and Harvard, Cambridge, MA 02142, USABastian SchillingDepartment of Dermatology, University Hospital, University Duisburg–Essen, 45147 Essen, GermanyDirk SchadendorfDepartment of Dermatology, University Hospital, University Duisburg–Essen, 45147 Essen, GermanyLevi A. GarrawayBroad Institute of MIT and Harvard, Cambridge, MA 02142, USAVladimir MakarovHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USANaiyer A. RizviHematology/Oncology Division, 177 Fort Washington Avenue, Columbia University, New York, NY 10032, USAAlexandra SnyderDepartment of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USAMatthew D. HellmannDepartment of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USATaha MerghoubDepartment of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USAJedd D. WolchokDepartment of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USASachet A. ShuklaBroad Institute of MIT and Harvard, Cambridge, MA 02142, USACatherine J. WuBroad Institute of MIT and Harvard, Cambridge, MA 02142, USAKarl S. PeggsCancer Immunology Unit, UCL Cancer Institute, UCL, London WC1E 6BT, UKTimothy A. ChanHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USASine Reker HadrupSection for Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark, 1970 Frederiksberg C, DenmarkSergio A. QuezadaCancer Immunology Unit, UCL Cancer Institute, UCL, London WC1E 6BT, UKCharles SwantonCancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK

2016en

ABI

Аннотация

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.

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Идентификаторы

DOI: 10.1126/science.aaf1490

Цитирования и источники

Цитирований: 2Использованных источников: 0

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