Immunogenic neoantigens derived from gene fusions stimulate T cell responses

Nat Med. 2019 May;25(5):767-775. doi: 10.1038/s41591-019-0434-2. Epub 2019 Apr 22.

Abstract

Anti-tumor immunity is driven by self versus non-self discrimination. Many immunotherapeutic approaches to cancer have taken advantage of tumor neoantigens derived from somatic mutations. Here, we demonstrate that gene fusions are a source of immunogenic neoantigens that can mediate responses to immunotherapy. We identified an exceptional responder with metastatic head and neck cancer who experienced a complete response to immune checkpoint inhibitor therapy, despite a low mutational load and minimal pre-treatment immune infiltration in the tumor. Using whole-genome sequencing and RNA sequencing, we identified a novel gene fusion and demonstrated that it produces a neoantigen that can specifically elicit a host cytotoxic T cell response. In a cohort of head and neck tumors with low mutation burden, minimal immune infiltration and prevalent gene fusions, we also identified gene fusion-derived neoantigens that generate cytotoxic T cell responses. Finally, analyzing additional datasets of fusion-positive cancers, including checkpoint-inhibitor-treated tumors, we found evidence of immune surveillance resulting in negative selective pressure against gene fusion-derived neoantigens. These findings highlight an important class of tumor-specific antigens and have implications for targeting gene fusion events in cancers that would otherwise be less poised for response to immunotherapy, including cancers with low mutational load and minimal immune infiltration.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm / genetics*
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / immunology
  • Gene Fusion
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / immunology
  • Head and Neck Neoplasms / therapy
  • Humans
  • Immunotherapy / methods*
  • NFI Transcription Factors / genetics
  • NFI Transcription Factors / immunology
  • Neoplasms / genetics
  • Neoplasms / immunology*
  • Neoplasms / therapy*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / immunology
  • Oncogene Proteins / genetics
  • Oncogene Proteins / immunology
  • Poly-ADP-Ribose Binding Proteins / genetics
  • Poly-ADP-Ribose Binding Proteins / immunology
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Proto-Oncogene Proteins c-myb / genetics
  • Proto-Oncogene Proteins c-myb / immunology
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Squamous Cell Carcinoma of Head and Neck / genetics
  • Squamous Cell Carcinoma of Head and Neck / immunology
  • Squamous Cell Carcinoma of Head and Neck / therapy
  • T-Lymphocytes, Cytotoxic / immunology*
  • Whole Genome Sequencing

Substances

  • AFF2 protein, human
  • Antigens, Neoplasm
  • Chromosomal Proteins, Non-Histone
  • Dek protein, human
  • MYB protein, human
  • NFI Transcription Factors
  • NFIB protein, human
  • Nuclear Proteins
  • Oncogene Proteins
  • PDCD1 protein, human
  • Poly-ADP-Ribose Binding Proteins
  • Programmed Cell Death 1 Receptor
  • Proto-Oncogene Proteins c-myb
  • Recombinant Fusion Proteins