@article{66ea2662039e4cb7a770680c0cc90d36,
title = "Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer",
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.",
author = "Balachandran, {Vinod P.} and Marta {\L}uksza and Zhao, {Julia N.} and Vladimir Makarov and Moral, {John Alec} and Romain Remark and Brian Herbst and Gokce Askan and Umesh Bhanot and Yasin Senbabaoglu and Wells, {Daniel K.} and Cary, {Charles Ian Ormsby} and Olivera Grbovic-Huezo and Marc Attiyeh and Benjamin Medina and Jennifer Zhang and Jennifer Loo and Joseph Saglimbeni and Mohsen Abu-Akeel and Roberta Zappasodi and Nadeem Riaz and Martin Smoragiewicz and {Larkin Kelley}, Z. and Olca Basturk and Mithat G{\"o}nen and Levine, {Arnold J.} and Allen, {Peter J.} and Fearon, {Douglas T.} and Miriam Merad and Sacha Gnjatic and Iacobuzio-Donahue, {Christine A.} and Wolchok, {Jedd D.} and Dematteo, {Ronald P.} and Chan, {Timothy A.} and Greenbaum, {Benjamin D.} and Taha Merghoub and Leach, {Steven D.} and Johns, {Amber L.} and {Scott Mead}, R. and Gill, {Anthony J.} and Chang, {David K.} and McKay, {Skye H.} and Chantrill, {Lorraine A.} and Chin, {Venessa T.} and Angela Chou and Humphris, {Jeremy L.} and Marina Pajic and Angela Steinmann and Mehreen Arshi and Ali Drury and Danielle Froio and Ashleigh Morgan and Paul Timpson and David Hermann and Claire Vennin and Sean Warren and Mark Pinese and Jianmin Wu and Pinho, {Andreia V.} and Katherine Tucker and Lesley Andrews and Samra, {Jaswinder S.} and Jennifer Arena and Nick Pavlakis and High, {Hilda A.} and Anubhav Mittal and Biankin, {Andrew V.} and Peter Bailey and Sancha Martin and Musgrove, {Elizabeth A.} and Jones, {Marc D.} and Craig Nourse and Jamieson, {Nigel B.} and Alina Stoita and David Williams and Allan Spigelman and Nicola Waddell and Pearson, {John V.} and Patch, {Ann Marie} and Katia Nones and Felicity Newell and Pamela Mukhopadhyay and Venkateswar Addala and Stephen Kazakoff and Oliver Holmes and Conrad Leonard and Scott Wood and Christina Xu and Grimmond, {Sean M.} and Oliver Hofmann and Wilson, {Peter J.} and Angelika Christ and Tim Bruxner and Ray Asghari and Merrett, {Neil D.} and Darren Pavey and Amitabha Das and Annabel Goodwin and Cosman, {Peter H.} and Kasim Ismail and Chelsie O{\textquoteright}connor and Cooper, {Caroline L.} and Peter Grimison and Kench, {James G.} and Charbel Sandroussi and Lam, {Vincent W.} and Duncan McLeod and Nagrial, {Adnan M.} and Judy Kirk and Virginia James and Michael Texler and Cindy Forest and Epari, {Krishna P.} and Mo Ballal and Fletcher, {David R.} and Sanjay Mukhedkar and Nikolajs Zeps and Maria Beilin and Kynan Feeney and Nguyen, {Nan Q.} and Ruszkiewicz, {Andrew R.} and Chris Worthley and John Chen and Brooke-Smith, {Mark E.} and Virginia Papangelis and Clouston, {Andrew D.} and Patrick Martin and Barbour, {Andrew P.} and O{\textquoteright}rourke, {Thomas J.} and Fawcett, {Jonathan W.} and Kellee Slater and Michael Hatzifotis and Peter Hodgkinson and Mehrdad Nikfarjam and Eshleman, {James R.} and Hruban, {Ralph H.} and Wolfgang, {Christopher L.} and Mary Hodgin and Aldo Scarpa and Lawlor, {Rita T.} and Stefania Beghelli and Vincenzo Corbo and Maria Scardoni and Claudio Bassi and {Australian Pancreatic Cancer Genome Initiative}",
year = "2017",
month = nov,
day = "23",
doi = "10.1038/nature24462",
language = "English",
volume = "551",
pages = "S12--S16",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7681",
}
