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|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.|
|Electronic Publication Date:||23-Nov-2017|
|Citation:||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, 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, QIMR Berghofer Medical Research Institute, 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, ARC-Net Centre for Applied Research on Cancer, 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. (2017). Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer.. Nature, 551 (7681), 512 - 516. doi:10.1038/nature24462|
|Pages:||512 - 516|
|Type of Material:||Journal Article|
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