期刊
SCIENCE
卷 351, 期 6280, 页码 1463-1469出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aaf1490
关键词
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资金
- CRUK (TRACERx)
- CRUK Lung Cancer Centre of Excellence
- Stand Up 2 Cancer Laura Ziskin prize (SU2C)
- Rosetrees Trust
- NovoNordisk Foundation [16584]
- Prostate Cancer Foundation
- Breast Cancer Research Foundation
- European Research Council (THESEUS)
- EU FP7 (PREDICT)
- CRUK Career Development Fellowship
- CRUK Biotherapeutic Programme Grant
- World Wide Cancer Research
- Cancer Research Institute
- Sam Keen Foundation
- TRACERx CRUK grant
- FP7-People-ITN [(2013)607722 - PloidyNet]
- Blavatnik Family Foundation
- NIH/National Heart, Lung, and Blood Institute [1R01CA155010-02]
- NIH/National Cancer Institute [1R01CA182461-01, 1R01CA184922-01]
- Cancer Research UK-UCL Centre
- CRUK-UCL Centre Clinical Research Fellowship
- Cancer Research UK-UCL Centre Cancer Immuno-Therapy Accelerator Award
- National Institute for Health Research
- University College London Hospitals Biomedical Research Centre
- Cancer Research UK University College London Experimental Cancer Medicine Centre
- Janssen
- Boerhinger Ingelheim
- Ventana
- Novartis
- Roche
- Sequenom
- Natera
- Grail
- Apogen Biotechnologies
- Epic Biosciences
- Sarah Cannon Research Institute
- Bristol-Myers Squibb
- Merck
- Amgen
- Geneocea
- OncoSpire
- Cancer Genetics
- Syapse
- Roche Ventana
- Takeda
- Third Rock Ventures
- Genentech
- AstraZeneca
- Neon
- Boehringer Ingelheim
- Foundation Medicine
- Warp Drive Bio
- Academy of Medical Sciences (AMS) [AMS-SGCL7-Murugaesu] Funding Source: researchfish
- Cancer Research UK [12100, 20466] Funding Source: researchfish
- Cancer Research UK
- Versus Arthritis [20265] Funding Source: researchfish
- Lundbeck Foundation [R181-2014-3828] Funding Source: researchfish
- National Institute for Health Research [CL-2011-18-001, CL-2015-17-002] Funding Source: researchfish
- The Francis Crick Institute [10002] Funding Source: researchfish
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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