title: Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia.
abstract: 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.
authors.affiliation: Cancer Vaccine Center and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Mohini
authors.initials: M
authors.lastname: Rajasagi
authors.affiliation: Cancer Vaccine Center and Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA;
authors.forename: Sachet A
authors.initials: SA
authors.lastname: Shukla
authors.affiliation: Cancer Vaccine Center and Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA;
authors.forename: Edward F
authors.initials: EF
authors.lastname: Fritsch
authors.affiliation: Cancer Vaccine Center and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Derin B
authors.initials: DB
authors.lastname: Keskin
authors.affiliation: Cancer Vaccine Center and Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA;
authors.forename: David
authors.initials: D
authors.lastname: DeLuca
authors.affiliation: Division of Medical Sciences: Biological and Biomedical Sciences, Harvard Medical School, Boston, MA;
authors.forename: Ellese
authors.initials: E
authors.lastname: Carmona
authors.affiliation: Cancer Vaccine Center and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Wandi
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA;
authors.forename: Carrie
authors.initials: C
authors.lastname: Sougnez
authors.affiliation: Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA;
authors.forename: Kristian
authors.initials: K
authors.lastname: Cibulskis
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA;
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Kristen
authors.initials: K
authors.lastname: Stevenson
authors.affiliation: Cancer Vaccine Center and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.affiliation: Cancer Vaccine Center and.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Brusic
authors.affiliation: Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA;
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.affiliation: Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA;
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.affiliation: Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA; Massachusetts General Hospital Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA; and.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA; The Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Nir
authors.initials: N
authors.lastname: Hacohen
authors.affiliation: Cancer Vaccine Center and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Wu
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000378:metabolism; D059472:Exome; D005260:Female; D006680:HLA Antigens / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D008297:Male; D009154:Mutation; D057285:Precision Medicine; D011485:Protein Binding; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens