Clonal Neoantigens Elicit T Cell Immunoreactivity and Sensitivity to Immune Checkpoint Blockade

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.

Science. 2016 Mar 3 [Epub]

Nicholas McGranahan,1,2,3  Andrew J. S. Furness,3,4 Rachel Rosenthal,3 Sofie Ramskov,5 Rikke Lyngaa,5 Sunil Kumar Saini,5 Mariam Jamal-Hanjani,3 Gareth A. Wilson,1,3 Nicolai J. Birkbak,1,3 Crispin T. Hiley,1,3 Thomas B. K. Watkins,1,3 Seema Shafi,3 Nirupa Murugaesu,3 Richard Mitter,1 Ayse U. Akarca,4,6 Joseph Linares,4,6 Teresa Marafioti,4,6 Jake Y. Henry,3,4 Eliezer M. Van Allen,7,8,9 Diana Miao,7,8 Bastian Schilling,10,11 Dirk Schadendorf,10,11 Levi A. Garraway,7,8,9 Vladimir Makarov,12 Naiyer A. Rizvi,13 Alexandra Snyder,14,15 Matthew D. Hellmann,14,15 Taha Merghoub,14,16 Jedd D. Wolchok,14,15,16 Sachet A. Shukla,7,8 Catherine J. Wu,7,8,17,18 Karl S. Peggs,3,4 Timothy A. Chan,12 Sine R. Hadrup,5 Sergio A. Quezada,3,4 and Charles Swanton1,3

1. The Francis Crick Institute, London, United Kingdom
2. Centre for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College London (UCL), London, United Kingdom
3. Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London, United Kingdom
4. Cancer Immunology Unit, UCL Cancer Institute, UCL, London, United Kingdom
5. Section for Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark, Frederiksberg C, Denmark
6. Department of Cellular Pathology, UCL, London, United Kingdom
7. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 
8. Broad Institute of MIT and Harvard, Cambridge, Massachusetts
9. Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts
10. Department of Dermatology, University Hospital, University Duisburg–Essen, Essen, Germany
11. German Cancer Consortium (DKTK), Heidelberg, Germany
12. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
13. Hematology/Oncology Division, 177 Fort Washington Avenue, Columbia University, New York, New York
14. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
15. Weill Cornell Medical College, New York, New York
16. Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York
17. Department of Medicine, Harvard Medical School, Boston, Massachusetts
18Department of Internal Medicine, Brigham and Woman’s Hospital, Boston, Massachusetts