| Contributors: |
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; 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; Johns, Al; Mead, R; Gill, Aj; Chang, Dk; Mckay, Sh; Chantrill, La; Chin, Vt; Chou, A; Humphris, Jl; Pajic, M; Steinmann, A; Arshi, M; Drury, A; Froio, D; Morgan, A; Timpson, P; Hermann, D; Vennin, C; Warren, S; Pinese, M; Wu, J; Pinho, Av; Tucker, K; Andrews, L; Samra, J; Arena, J; Pavlakis, N; High, Ha; Mittal, A; Biankin, Av; Bailey, P; Martin, S; Musgrove, Ea; Jones, Md; Nourse, C; Jamieson, Nb; Stoita, A; Williams, D; Spigelman, A; Waddell, N; Pearson, Jv; Patch, Am; Nones, K; Newell, F; Mukhopadhyay, P; Addala, V; Kazakoff, S; Holmes, O; Leonard, C; Wood, S; Xu, C; Grimmond, Sm; Hofmann, O; Wilson, Pj; Christ, A; Bruxner, T; Asghari, R; Merrett, Nd |
| Description: |
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. |