Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer Journal Article
| Authors: | Balachandran, V. P.; Luksza, 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.; Australian Pancreatic Cancer Genome Initiative; 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.; Leach, S. D. |
| Article 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. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. |
| Keywords: | immunohistochemistry; survival; adult; clinical article; controlled study; aged; unclassified drug; human cell; cd8+ t lymphocyte; protein analysis; gene expression; gene frequency; peptide; cancer survivor; antigen; biomarker; immunogenicity; epitope; pancreas adenocarcinoma; immunity; ca 125 antigen; tumor; model; t lymphocyte activation; disease treatment; biophysics; clone; t lymphocyte antigen; homology; cells and cell components; cancer; human; male; female; priority journal; article; whole exome sequencing; neoantigen |
| Journal Title: | Nature |
| Volume: | 551 |
| Issue: | 7681 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2017-11-23 |
| Start Page: | 512 |
| End Page: | 516 |
| Language: | English |
| DOI: | 10.1038/nature24462 |
| PROVIDER: | scopus |
| PUBMED: | 29132146 |
| PMCID: | PMC6145146 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 January 2018 -- Source: Scopus |
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