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

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...

Full description

Saved in:
Bibliographic Details
Published in:Nature (London) 2017-11, Vol.551 (7681), p.512-516
Main Authors: Balachandran, Vinod P, Łuksza, Marta, Zhao, Julia N, Makarov, Vladimir, Moral, John Alec, Remark, Romain, Herbst, Brian, Askan, Gokce, Bhanot, Umesh, Senbabaoglu, Yasin, Wells, Daniel K, Cary, Charles Ian Ormsby, Grbovic-Huezo, Olivera, Attiyeh, Marc, Medina, Benjamin, Zhang, Jennifer, Loo, Jennifer, Saglimbeni, Joseph, Abu-Akeel, Mohsen, Zappasodi, Roberta, Riaz, Nadeem, Smoragiewicz, Martin, Kelley, Z Larkin, Basturk, Olca, Gönen, Mithat, Levine, Arnold J, Allen, Peter J, Fearon, Douglas T, Merad, Miriam, Gnjatic, Sacha, Iacobuzio-Donahue, Christine A, Wolchok, Jedd D, DeMatteo, Ronald P, Chan, Timothy A, Greenbaum, Benjamin D, Merghoub, Taha, Leach, Steven D
Format: Article
Language:English
Subjects:
Adenocarcinoma
Adenocarcinoma - blood
Adenocarcinoma - genetics
Adenocarcinoma - immunology
Antigens
Antigens, Neoplasm - genetics
Antigens, Neoplasm - immunology
Bacterial Proteins - blood
Bacterial Proteins - genetics
Bacterial Proteins - immunology
Bioindicators
Biomarkers
Biophysics
CA-125 Antigen - genetics
CA-125 Antigen - immunology
Cancer
Cancer Survivors
CD8 antigen
Cell activation
Chemotherapy
Computer Simulation
Cross Reactions - genetics
Cross Reactions - immunology
Epitopes
Exome Sequencing
Genomes
Health aspects
Homology
Humans
Immunity
Immunogenicity
Immunotherapy
Infectious diseases
Lymphocytes
Lymphocytes T
Medical research
Membrane Proteins - genetics
Membrane Proteins - immunology
Metastases
Microorganisms
Neoantigens
Pancreatic cancer
Pancreatic Neoplasms - blood
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - immunology
Patients
Peptides
Physiological aspects
Prognosis
Survival Analysis
T cell receptors
T-Lymphocytes, Cytotoxic - cytology
T-Lymphocytes, Cytotoxic - immunology
Transcription
Tumors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0028-0836
1476-4687
DOI:10.1038/nature24462