Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Nature. 2017 Nov 23;551(7681):512-516. doi: 10.1038/nature24462. Epub 2017 Nov 8.

Abstract

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies.

Publication types

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

MeSH terms

  • Adenocarcinoma / blood
  • Adenocarcinoma / genetics
  • Adenocarcinoma / immunology
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / immunology*
  • Bacterial Proteins / blood
  • Bacterial Proteins / genetics
  • Bacterial Proteins / immunology*
  • CA-125 Antigen / genetics
  • CA-125 Antigen / immunology
  • Cancer Survivors*
  • Computer Simulation
  • Cross Reactions / genetics
  • Cross Reactions / immunology*
  • Humans
  • Immunotherapy
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Pancreatic Neoplasms / blood
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / immunology*
  • Prognosis
  • Survival Analysis
  • T-Lymphocytes, Cytotoxic / cytology
  • T-Lymphocytes, Cytotoxic / immunology*
  • Whole Exome Sequencing

Substances

  • Antigens, Neoplasm
  • Bacterial Proteins
  • CA-125 Antigen
  • MUC16 protein, human
  • Membrane Proteins