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

Vinod P. Balachandran, Marta Luksza, 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, Australian Pancreatic Cancer Genome Initiative, Amber L. Johns, R. Scott Mead, Anthony J. Gill, David K. Chang, Skye H. McKay, Lorraine A. Chantrill, Venessa T. Chin, Angela Chou, Jeremy L. Humphris, Marina Pajic, Angela Steinmann, Mehreen Arshi, Ali Drury, Danielle Froio, Ashleigh Morgan, Paul Timpson, David Hermann, Claire Vennin, Sean Warren, Mark Pinese, Jianmin Wu, Andreia V. Pinho, Katherine Tucker, Lesley Andrews, Jaswinder S. Samra, Jennifer Arena, Nick Pavlakis, Hilda A. High, Anubhav Mittal, Andrew V. Biankin, Peter Bailey, Sancha Martin, Elizabeth A. Musgrove, Marc D. Jones, Craig Nourse, Nigel B. Jamieson, Alina Stoita, David Williams, Allan Spigelman, Nicola Waddell, John V. Pearson, Ann-Marie Patch, Katia Nones, Felicity Newell, Pamela Mukhopadhyay, Venkateswar Addala, Stephen Kazakoff, Oliver Holmes, Conrad Leonard, Scott Wood, Christina Xu, Sean M. Grimmond, Oliver Hofmann, Peter J. Wilson, Angelika Christ, Tim Bruxner, Ray Asghari, Neil D. Merrett, 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

Research output: Contribution to journalArticlepeer-review

860 Citations (Scopus)

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 survivors1,2 , 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 wholeexome 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)512-516
Number of pages5
JournalNature
Volume551
Issue number7681
DOIs
Publication statusPublished - 2017

Fingerprint

Dive into the research topics of 'Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer'. Together they form a unique fingerprint.

Cite this