Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade Academic Article uri icon

Overview

MeSH Major

  • Adenocarcinoma
  • Antigens, Neoplasm
  • CD4-Positive T-Lymphocytes
  • Immunologic Surveillance
  • Lung Neoplasms

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.

authors

publication date

  • March 25, 2016

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4984254

Digital Object Identifier (DOI)

  • 10.1126/science.aaf1490

PubMed ID

  • 26940869

Additional Document Info

start page

  • 1463

end page

  • 9

volume

  • 351

number

  • 6280