Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade
Year: 2016
Type: article
Study design: Observational Study
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.
Source: Science
Authors: Nicholas McGranahan, Andrew J. S. Furness, Rachel Rosenthal, Sofie Ramskov, Rikke 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 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
Institutions: The Francis Crick Institute, Cancer Research UK, University College London, Technical University of Denmark, Broad Institute, Dana-Farber Cancer Institute, Deutsches Konsortium für Translationale Krebsforschung, University of Duisburg-Essen, Memorial Sloan Kettering Cancer Center, Columbia University Irving Medical Center, Columbia University, Weill Cornell Medicine, Brigham and Women's Hospital, Harvard University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Prostate Cancer Foundation, Breast Cancer Research Foundation, Leukemia and Lymphoma Society, Francis Crick Institute, Blavatnik Family Foundation, Cancer Research UK, National Institute for Health and Care Research, Novo Nordisk UK Research Foundation, Academy of Medical Sciences, Rosetrees Trust, Lundbeckfonden, Seventh Framework Programme, National Heart, Lung, and Blood Institute, National Cancer Institute, H2020 European Research Council
OpenAlex ID: W2291298003