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

Vinod P. Balachandran, Marta Łuksza, Julia N. Zhao, Vladimir Makarov, John Alec Moral, Romain Remark, Brian Herbst, Gokce Askan, Umesh Bhanot, Yasin Senbabaoglu, Daniel K. Wells, Charles Ian Ormsby Cary, Olivera Grbovic-Huezo, Marc Attiyeh, Benjamin Medina, Jennifer Zhang, Jennifer Loo, Joseph Saglimbeni, Mohsen Abu-Akeel, Roberta ZappasodiNadeem Riaz, Martin Smoragiewicz, Z. Larkin Kelley, Olca Basturk, Mithat Gönen, Arnold J. Levine, Peter J. Allen, Douglas T. Fearon, Miriam Merad, Sacha Gnjatic, Christine A. Iacobuzio-Donahue, Jedd D. Wolchok, Ronald P. Dematteo, Timothy A. Chan, Benjamin D. Greenbaum, Taha Merghoub, Steven D. Leach, Australian Pancreatic Cancer Genome Initiative

Research output: Contribution to journalArticleResearchpeer-review

512 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)S12-S16
Number of pages5
Issue number7681
Publication statusPublished - 23 Nov 2017
Externally publishedYes

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