Journal
BLOOD
Volume 124, Issue 3, Pages 453-462Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-04-567933
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Funding
- National Institutes of Health, National Human Genome Research Institute [U54HG003067]
- National Cancer Institute [1RO1CA155010-02]
- National Heart, Lung, and Blood Institute [5R01HL103532-03]
- Blavatinik Family Foundation
- Leukemia and Lymphoma Translational Research Program
- Innovative Research Grant for Stand-Up to Cancer/American Association of Cancer Research
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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 similar to 22 mutated HLA-binding peptides per leukemia (derived from similar to 16 missense mutations) and experimentally confirmed HLA binding for similar to 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.
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