학술논문
Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer
Document Type
Academic Journal
Author
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.; Ormsby Cary, Charles Ian; Grbovic-Huezo, Olivera; Attiyeh, Marc; Medina, Benjamin; Zhang, Jennifer; Loo, Jennifer; Saglimbeni, Joseph; Abu-Akeel, Mohsen; Zappasodi, Roberta; Riaz, Nadeem; Smoragiewicz, Martin; Kelley, Larkin Z.; Basturk, Olca; Johns, Amber L.; Mead, Scott R.; Gill, Anthony J.; Chang, David K.; McKay, Skye H.; Chantrill, Lorraine A.; Chin, Venessa T.; Chou, Angela; Humphris, Jeremy L.; Pajic, Marina; Steinmann, Angela; Arshi, Mehreen; Drury, Ali; Froio, Danielle; Morgan, Ashleigh; Timpson, Paul; Hermann, David; Vennin, Claire; Warren, Sean; Pinese, Mark; Wu, Jianmin; Pinho, Andreia V.; Tucker, Katherine; Andrews, Lesley; Samra, Jaswinder S.; Arena, Jennifer; Pavlakis, Nick; High, Hilda A.; Mittal, Anubhav; Biankin, Andrew V.; Bailey, Peter; Martin, Sancha; Musgrove, Elizabeth A.; Jones, Marc D.; Nourse, Craig; Jamieson, Nigel B.; Stoita, Alina; Williams, David; Spigelman, Allan; Waddell, Nicola; Pearson, John V.; Patch, Ann-Marie; Nones, Katia; Newell, Felicity; Mukhopadhyay, Pamela; Addala, Venkateswar; Kazakoff, Stephen; Holmes, Oliver; Leonard, Conrad; Wood, Scott; Xu, Christina; Grimmond, Sean M.; Hofmann, Oliver; Wilson, Peter J.; Christ, Angelika; Bruxner, Tim; Asghari, Ray; Merrett, Neil D.; Pavey, Darren; Das, Amitabha; Goodwin, Annabel; Cosman, Peter H.; Ismail, Kasim; O’Connor, Chelsie; Cooper, Caroline L.; Grimison, Peter; Kench, James G.; Sandroussi, Charbel; Lam, Vincent W.; McLeod, Duncan; Nagrial, Adnan M.; Kirk, Judy; James, Virginia; Texler, Michael; Forest, Cindy; Epari, Krishna P.; Ballal, Mo; Fletcher, David R.; Mukhedkar, Sanjay; Zeps, Nikolajs; Beilin, Maria; Feeney, Kynan; Nguyen, Nan Q.; Ruszkiewicz, Andrew R.; Worthley, Chris; Chen, John; Brooke-Smith, Mark E.; Papangelis, Virginia; Clouston, Andrew D.; Martin, Patrick; Barbour, Andrew P.; O’Rourke, Thomas J.; Fawcett, Jonathan W.; Slater, Kellee; Hatzifotis, Michael; Hodgkinson, Peter; Nikfarjam, Mehrdad; Eshleman, James R.; Hruban, Ralph H.; Wolfgang, Christopher L.; Hodgin, Mary; Scarpa, Aldo; Lawlor, Rita T.; Beghelli, Stefania; Corbo, Vincenzo; Scardoni, Maria; Bassi, Claudio; 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.
Source
Nature. Nov 23, 2017 551(7681):512-516
Subject
Language
English
ISSN
0028-0836
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.