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., Gonen, 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. (November 2017) Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature, 551 (7681). pp. 512-516. 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.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer > metastasis diseases & disorders > cancer > cancer types > pancreatic cancer |
| CSHL Authors: | |
| Communities: | CSHL labs > Fearon lab CSHL Cancer Center Program > Cellular Communication in Cancer Program |
| Depositing User: | Matt Covey |
| Date: | 23 November 2017 |
| Date Deposited: | 15 Nov 2017 16:57 |
| Last Modified: | 06 Jul 2021 18:31 |
| PMCID: | PMC6145146 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/35670 |
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