Dataset Information

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

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.

SUBMITTER: Balachandran VP

PROVIDER: S-EPMC6145146 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Balachandran Vinod P VP Łuksza Marta M Zhao Julia N JN Makarov Vladimir V Moral John Alec JA Remark Romain R Herbst Brian B Askan Gokce G Bhanot Umesh U Senbabaoglu Yasin Y Wells Daniel K DK Cary Charles Ian Ormsby CIO Grbovic-Huezo Olivera O Attiyeh Marc M Medina Benjamin B Zhang Jennifer J Loo Jennifer J Saglimbeni Joseph J Abu-Akeel Mohsen M Zappasodi Roberta R Riaz Nadeem N Smoragiewicz Martin M Kelley Z Larkin ZL Basturk Olca O Gönen Mithat M Levine Arnold J AJ Allen Peter J PJ Fearon Douglas T DT Merad Miriam M Gnjatic Sacha S Iacobuzio-Donahue Christine A CA Wolchok Jedd D JD DeMatteo Ronald P RP Chan Timothy A TA Greenbaum Benjamin D BD Merghoub Taha T Leach Steven D SD

Nature 20171108 7681

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 predict ...[more]

PMID: 29132146

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Dataset Information

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

Publications

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

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