Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Balachandran, V. P. et al. (2017) Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature, 551, pp. 512-516. (doi: 10.1038/nature24462) (PMID:29132146) (PMCID:PMC6145146)

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 survivors1,2, 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.

• Item Type: Articles (Letter)
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Jamieson, Professor Nigel and Biankin, Professor Andrew and Martin, Ms Sancha and Nourse, Dr Craig and Jones, Mr Marc and Bailey, Dr Peter and Musgrove, Dr Elizabeth and Chang, Professor David
• Authors: Balachandran, V. P., Łuksza, M., Zhao, J. N., Makarov, V., Moral, J. A., Remark, R., Herbst, B., Askan, G., Bhanot, U., Senbabaoglu, Y., Wells, D. K., Cary, C. I. O., Grbovic-Huezo, O., Attiyeh, M., Medina, B., Zhang, J., Loo, J., Saglimbeni, J., Abu-Akeel, M., Zappasodi, R., Riaz, N., Smoragiewicz, M., Kelley, Z. L., Basturk, O., Johns, A. L., Mead, R. S., Gill, A. J., Chang, D. K., McKay, S. H., Chantrill, L. A., Chin, V. T., Chou, A., Humphris, J. L., 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, A. V., Mead, R. S., Tucker, K., Andrews, L., Gill, A. J., Samra, J. S., Arena, J., Pavlakis, N., High, H. A., Mittal, A., Biankin, A. V., Bailey, P., Martin, S., Musgrove, E. A., Jones, M. D., Nourse, C., Jamieson, N. B., Chou, A., Chantrill, L. A., Stoita, A., Williams, D., Spigelman, A., Waddell, N., Pearson, J. V., Patch, A.-M., Nones, K., Newell, F., Mukhopadhyay, P., Addala, V., Kazakoff, S., Holmes, O., Leonard, C., Wood, S., Xu, C., Grimmond, S. M., Hofmann, O., Wilson, P. J., Christ, A., Bruxner, T., Asghari, R., Merrett, N. D., Pavey, D., Das, A., Goodwin, A., Cosman, P. H., Ismail, K., O’Connor, C., Cooper, C. L., Goodwin, A., Grimison, P., Kench, J. G., Sandroussi, C., Lam, V. W., McLeod, D., Nagrial, A. M., Kirk, J., James, V., Texler, M., Forest, C., Epari, K. P., Ballal, M., Fletcher, D. R., Mukhedkar, S., Zeps, N., Beilin, M., Feeney, K., Nguyen, N. Q., Ruszkiewicz, A. R., Worthley, C., Chen, J., Brooke-Smith, M. E., Papangelis, V., Clouston, A. D., Martin, P., Barbour, A. P., O’Rourke, T. J., Fawcett, J. W., Slater, K., Hatzifotis, M., Hodgkinson, P., Nikfarjam, M., Eshleman, J. R., Hruban, R. H., Wolfgang, C. L., Hodgin, M., Scarpa, A., Lawlor, R. T., Beghelli, S., Corbo, V., Scardoni, M., Bassi, C., Gönen, M., Levine, A. J., Allen, P. J., Fearon, D. T., Merad, M., Gnjatic, S., Iacobuzio-Donahue, C. A., Wolchok, J. D., DeMatteo, R. P., Chan, T. A., Greenbaum, B. D., Merghoub, T., and Leach, S. D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature
• Publisher: Nature Publishing Group
• ISSN: 0028-0836
• ISSN (Online): 1476-4687
• Published Online: 08 November 2017
• Copyright Holders: Copyright © 2017 Macmillan Publishers Limited, part of Springer Nature