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Science. 2016 Mar 25;351(6280):1463-9. doi: 10.1126/science.aaf1490. Epub 2016 Mar 3.

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

Author information

1
The Francis Crick Institute, London WC2A 3LY, UK. Centre for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College London (UCL), London WC1E 6BT, UK. Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK.
2
Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK. Cancer Immunology Unit, UCL Cancer Institute, UCL, London WC1E 6BT, UK.
3
Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK.
4
Section for Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark, 1970 Frederiksberg C, Denmark.
5
The Francis Crick Institute, London WC2A 3LY, UK. Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK.
6
The Francis Crick Institute, London WC2A 3LY, UK.
7
Cancer Immunology Unit, UCL Cancer Institute, UCL, London WC1E 6BT, UK. Department of Cellular Pathology, UCL, London WC1E 6BT, UK.
8
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
9
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
10
Department of Dermatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany. German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.
11
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
12
Hematology/Oncology Division, 177 Fort Washington Avenue, Columbia University, New York, NY 10032, USA.
13
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA.
14
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
15
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
16
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Department of Internal Medicine, Brigham and Woman's Hospital, Boston, MA 02115, USA.
17
Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK. Cancer Immunology Unit, UCL Cancer Institute, UCL, London WC1E 6BT, UK. s.quezada@ucl.ac.uk charles.swanton@crick.ac.uk.
18
The Francis Crick Institute, London WC2A 3LY, UK. Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK. s.quezada@ucl.ac.uk charles.swanton@crick.ac.uk.

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.

PMID:
26940869
PMCID:
PMC4984254
DOI:
10.1126/science.aaf1490
[Indexed for MEDLINE]
Free PMC Article

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