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.
Balachandran, VP; Łuksza, M; Zhao, JN; Makarov, V; Moral, JA; Remark, R; Herbst, B; Askan, G; Bhanot, U; Senbabaoglu, Y; Wells, DK; Cary, CIO; Grbovic-Huezo, O; Attiyeh, M; Medina, B; Zhang, J; Loo, J; Saglimbeni, J; Abu-Akeel, M; Zappasodi, R; Riaz, N; Smoragiewicz, M; Kelley, ZL; 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, ; 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, M; Levine, AJ; Allen, PJ; Fearon, DT; Merad, M; Gnjatic, S; Iacobuzio-Donahue, CA; Wolchok, JD; DeMatteo, RP; Chan, TA; Greenbaum, BD; Merghoub, T; Leach, SD
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