Identification of Glycopeptides as Posttranslationally Modified Neoantigens in Leukemia.
Leukemias are highly immunogenic, but they have a low mutational load, providing few mutated peptide targets. Thus, the identification of alternative neoantigens is a pressing need. Here, we identify 36 MHC class I-associated peptide antigens with O-linked β-N-acetylglucosamine (O-GlcNAc) modifications as candidate neoantigens, using three experimental approaches. Thirteen of these peptides were also detected with disaccharide units on the same residues and two contain either mono- and/or di-methylated arginine residues. A subset were linked with key cancer pathways, and these peptides were shared across all of the leukemia patient samples tested (5/5). Seven of theO-GlcNAc peptides were synthesized and five (71%) were shown to be associated with multifunctional memory T-cell responses in healthy donors. AnO-GlcNAc-specific T-cell line specifically killed autologous cells pulsed with the modified peptide, but not the equivalent unmodified peptide. Therefore, these posttranslationally modified neoantigens provide logical targets for cancer immunotherapy.Cancer Immunol Res; 5(5); 376-84. ©2017 AACR.
Department of Chemistry, University of Virginia, Charlottesville, Virginia.
Stacy A
SA
Malaker
Department of Clinical Immunology, University of Birmingham, Birmingham, United Kingdom.
Sarah A
SA
Penny
Department of Clinical Immunology, University of Birmingham, Birmingham, United Kingdom.
Lora G
LG
Steadman
Department of Chemistry, University of Virginia, Charlottesville, Virginia.
Paisley T
PT
Myers
Department of Clinical Immunology, University of Birmingham, Birmingham, United Kingdom.
Justin C
JC
Loke
Department of Clinical Immunology, University of Birmingham, Birmingham, United Kingdom.
Manoj
M
Raghavan
Department of Chemistry, University of Virginia, Charlottesville, Virginia.
Dina L
DL
Bai
Department of Chemistry, University of Virginia, Charlottesville, Virginia.
Jeffrey
J
Shabanowitz
Department of Chemistry, University of Virginia, Charlottesville, Virginia.|Department of Pathology, University of Virginia, Charlottesville, Virginia.
Donald F
DF
Hunt
Department of Clinical Immunology, University of Birmingham, Birmingham, United Kingdom. mcobbold@mgh.harvard.edu.|Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Charlestown, Massachusetts.
Mark
M
Cobbold
D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D006020:Glycopeptides / Q000276:immunology* / Q000378:metabolism; D006031:Glycosylation; D015793:HLA-B7 Antigen / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000276:immunology*; D008745:Methylation; D011499:Protein Processing, Post-Translational; D013601:T-Lymphocytes / Q000276:immunology
D000951:Antigens, Neoplasm; D006020:Glycopeptides; C477444:HLA-B*07:02 antigen; D015793:HLA-B7 Antigen