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

Authors
  • Balachandran, Vinod P1, 2, 3
  • Łuksza, Marta4
  • Zhao, Julia N1, 2, 3
  • Makarov, Vladimir5, 6
  • Moral, John Alec1, 2, 3
  • Remark, Romain7
  • Herbst, Brian2
  • Askan, Gokce2, 8
  • Bhanot, Umesh8
  • Senbabaoglu, Yasin9
  • Wells, Daniel K10
  • Cary, Charles Ian Ormsby10
  • Grbovic-Huezo, Olivera2
  • Attiyeh, Marc1, 2
  • Medina, Benjamin1
  • Zhang, Jennifer1
  • Loo, Jennifer1
  • Saglimbeni, Joseph2
  • Abu-Akeel, Mohsen9
  • Zappasodi, Roberta9
  • And 17 more
  • 1 Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • 2 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • 3 Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • 4 The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, New Jersey, USA. , (Jersey)
  • 5 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • 6 Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • 7 Tisch Cancer Institute, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 8 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • 9 Swim Across America/Ludwig Collaborative Laboratory, New York, New York, USA.
  • 10 Parker Institute for Cancer Immunotherapy, San Francisco, California, USA.
  • 11 Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • 12 Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.
  • 13 Cold Spring Harbor Laboratory, New York, New York, USA.
  • 14 Department of Microbiology and Immunology, Weill Cornell Medical School, New York, New York, USA.
  • 15 Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • 16 Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • 17 Weill Cornell Medical College, Cornell University, New York, New York, USA.
  • 18 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • 19 Tisch Cancer Institute, Departments of Medicine, Hematology and Medical Oncology, Oncological Sciences, and Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 20 Dartmouth Norris Cotton Cancer Center, Lebanon, New Hampshire, USA. , (Lebanon)
Type
Published Article
Journal
Nature
Publisher
Springer Nature
Publication Date
Nov 23, 2017
Volume
551
Issue
7681
Pages
512–516
Identifiers
DOI: 10.1038/nature24462
PMID: 29132146
Source
Medline
License
Unknown

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.

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