title: Alloreactive cytotoxic T cells provide means to decipher the immunopeptidome and reveal a plethora of tumor-associated self-epitopes.
abstract: HLA molecules presenting peptides derived from tumor-associated self-antigens (self-TAA) are attractive targets for T-cell-based immunotherapy of cancer. However, detection of such epitopes is hampered by self-tolerance and limitations in the sensitivity of mass spectrometry. Here, we used T cells from HLA-A2-negative donors as tools to detect HLA-A2-bound peptides from two leukemia-associated differentiation antigens; CD20 and the previously undescribed cancer target myeloperoxidase. A high-throughput platform for epitope discovery was designed using dendritic cells cotransfected with full-length transcripts of self-TAA and HLA-A2 to allow presentation of all naturally processed peptides from a predefined self-protein on foreign HLA. Antigen-reactive T cells were directly detected using panels of color-coded peptide-HLA multimers containing epitopes predicted by a computer algorithm. Strikingly, cytotoxic T cells were generated against 37 out of 50 peptides predicted to bind HLA-A2. Among these, 36 epitopes were previously undescribed. The allorestricted T cells were exquisitely peptide- and HLA-specific and responded strongly to HLA-A2-positive leukemic cells with endogenous expression of CD20 or myeloperoxidase. These results indicate that the repertoire of self-peptides presented on HLA class I has been underestimated and that a wealth of self-TAA can be targeted by T cells when using nontolerized T-cell repertoires.
authors.affiliation: Department of Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, N-0310 Oslo, Norway.
authors.forename: Shraddha
authors.initials: S
authors.lastname: Kumari
authors.forename: Sébastien
authors.initials: S
authors.lastname: Wälchli
authors.forename: Lars-Egil
authors.initials: LE
authors.lastname: Fallang
authors.forename: Weiwen
authors.initials: W
authors.lastname: Yang
authors.forename: Fridtjof
authors.initials: F
authors.lastname: Lund-Johansen
authors.forename: Ton N
authors.initials: TN
authors.lastname: Schumacher
authors.forename: Johanna
authors.initials: J
authors.lastname: Olweus
mesh_terms: D000465:Algorithms; D017951:Antigen Presentation; D018951:Antigens, CD20 / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000737:chemistry; D001324:Autoantigens / Q000737:chemistry; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry*; D005434:Flow Cytometry; D018922:HL-60 Cells; D015789:HLA-A2 Antigen / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007107:Immune System; D007167:Immunotherapy; D013058:Mass Spectrometry; D009369:Neoplasms / Q000276:immunology*; D010455:Peptides / Q000737:chemistry*; D009195:Peroxidase / Q000737:chemistry; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology*
chemical_list: D018951:Antigens, CD20; D000951:Antigens, Neoplasm; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D010455:Peptides; D012333:RNA, Messenger; D009195:Peroxidase