Genome sequencing has revealed a large number of shared and personal somatic mutations across human cancers. In principle, any genetic alteration affecting a protein-coding region has the potential to generate mutated peptides that are presented by surface HLA class I proteins that might be recognized by cytotoxic T cells. To test this possibility, we implemented a streamlined approach for the prediction and validation of such neoantigens derived from individual tumors and presented by patient-specific HLA alleles. We applied our computational pipeline to 91 chronic lymphocytic leukemias (CLLs) that underwent whole-exome sequencing (WES). We predicted ~22 mutated HLA-binding peptides per leukemia (derived from ~16 missense mutations) and experimentally confirmed HLA binding for ~55% of such peptides. Two CLL patients that achieved long-term remission following allogeneic hematopoietic stem cell transplantation were monitored for CD8+ T-cell responses against predicted or confirmed HLA-binding peptides. Long-lived cytotoxic T-cell responses were detected against peptides generated from personal tumor mutations in ALMS1, C6ORF89, and FNDC3B presented on tumor cells. Finally, we applied our computational pipeline to WES data (N = 2488 samples) across 13 different cancer types and estimated dozens to thousands of predicted neoantigens per individual tumor, suggesting that neoantigens are frequent in most tumors. © 2014 by The American Society of Hematology.
CITATION STYLE
Rajasagi, M., Shukla, S. A., Fritsch, E. F., Keskin, D. B., DeLuca, D., Carmona, E., … Wu, C. J. (2014). Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia. Blood, 124(3), 453–462. https://doi.org/10.1182/blood-2014-04-567933
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