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


Authors: McGranahan, N.; Furness, A. J. S.; Rosenthal, R.; Ramskov, S.; Lyngaa, R.; Saini, S. K.; Jamal-Hanjani, M.; Wilson, G. A.; Birkbak, N. J.; Hiley, C. T.; Watkins, T. B. K.; Shafi, S.; Murugaesu, N.; Mitter, R.; Akarca, A. U.; Linares, J.; Marafioti, T.; Henry, J. Y.; Van Allen, E. M.; Miao, D.; Schilling, B.; Schadendorf, D.; Garraway, L. A.; Makarov, V.; Rizvi, N. A.; Snyder, A.; Hellmann, M. D.; Merghoub, T.; Wolchok, J. D.; Shukla, S. A.; Wu, C. J.; Peggs, K. S.; Chan, T. A.; Hadrup, S. R.; Quezada, S. A.; Swanton, C.
Article Title: Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade
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.
Journal Title: Science
Volume: 351
Issue: 6280
ISSN: 0036-8075
Publisher: American Association for the Advancement of Science  
Date Published: 2016-03-25
Start Page: 1463
End Page: 1469
Language: English
DOI: 10.1126/science.aaf1490
PROVIDER: scopus
PUBMED: 26940869
PMCID: PMC4984254
DOI/URL:
Notes: Article -- Export Date: 2 May 2016 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Timothy Chan
    228 Chan
  2. Jedd D Wolchok
    674 Wolchok
  3. Taha Merghoub
    211 Merghoub
  4. Matthew David Hellmann
    176 Hellmann
  5. Vladimir Makarov
    34 Makarov