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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 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.

Type Journal
ISBN 1476-4687 (Electronic) 0028-0836 (Linking)
Authors Balachandran, V. P.; Luksza, M.; Zhao, J. N.; Makarov, V.; Moral, J. A.; Remark, R.; Herbst, B.; Askan, G.; Bhanot, U.; Senbabaoglu, Y.; Wells, D. K.; Cary, C. I. O.; Grbovic-Huezo, O.; Attiyeh, M.; Medina, B.; Zhang, J.; Loo, J.; Saglimbeni, J.; Abu-Akeel, M.; Zappasodi, R.; Riaz, N.; Smoragiewicz, M.; Kelley, Z. L.; Basturk, O.; Australian Pancreatic Cancer Genome, Initiative; Garvan Institute of Medical, Research; Prince of Wales, Hospital; Royal North Shore, Hospital; University of, Glasgow; St Vincent's, Hospital; Institute, Qimr Berghofer Medical Research; University of Melbourne, Centre for Cancer Research; University of Queensland, Institute for Molecular Bioscience; Bankstown, Hospital; Liverpool, Hospital; Royal Prince Alfred Hospital, Chris O'Brien Lifehouse; Westmead, Hospital; Fremantle, Hospital; St John of God, Healthcare; Royal Adelaide, Hospital; Flinders Medical, Centre; Envoi, Pathology; Princess Alexandria, Hospital; Austin, Hospital; Johns Hopkins Medical, Institutes; Cancer, A. RC-Net Centre for Applied Research on; Gonen, M.; Levine, A. J.; Allen, P. J.; Fearon, D. T.; Merad, M.; Gnjatic, S.; Iacobuzio-Donahue, C. A.; Wolchok, J. D.; DeMatteo, R. P.; Chan, T. A.; Greenbaum, B. D.; Merghoub, T.; Leach, S. D.
Publisher Name NATURE
Published Date 2017-11-23
Published Volume 551
Published Issue 7681
Published Pages 512-516
Status Published in-print
DOI 10.1038/nature24462
URL link to publisher's version