title: Therapeutic targeting of the BCR-associated protein CD79b in a TCR-based approach is hampered by aberrant expression of CD79b.
abstract: Immunotherapy of B-cell malignancies using CD19-targeted chimeric antigen receptor-transduced T cells or CD20-targeted therapeutic monoclonal antibodies has shown clinical efficacy. However, refractory disease and the emergence of antigen-loss tumor escape variants after treatment demonstrate the need to target additional antigens. Here we aimed to target the B-cell receptor-associated protein CD79b by a T-cell receptor (TCR)-based approach. Because thymic selection depletes high-avidity T cells recognizing CD79b-derived peptides presented in self-HLA molecules, we aimed to isolate T cells recognizing these peptides presented in allogeneic HLA. Peptide-HLA tetramers composed of CD79b peptides bound to either HLA-A2 or HLA-B7 were used to isolate T-cell clones from HLA-A*0201 and B*0702-negative individuals. For 3 distinct T-cell clones, CD79b specificity was confirmed through CD79b gene transduction and CD79b-specific shRNA knockdown. The CD79b-specific T-cell clones were highly reactive against CD79b-expressing primary B-cell malignancies, whereas no recognition of nonhematopoietic cells was observed. Although lacking CD79b-cell surface expression, intermediate reactivity toward monocytes, hematopoietic progenitor cells, and T-cells was observed. Quantitative reverse transcriptase polymerase chain reaction revealed low CD79b gene expression in these cell types. Therefore, aberrant gene expression must be taken into consideration when selecting common, apparently lineage-specific self-antigens as targets for TCR-based immunotherapies.
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: Lorenz
authors.initials: L
authors.lastname: Jahn
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands; Department of Hematopoiesis, Sanquin Research, Amsterdam, The Netherlands; and.
authors.forename: Pleun
authors.initials: P
authors.lastname: Hombrink
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Chopie
authors.initials: C
authors.lastname: Hassan
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: Michel G D
authors.initials: MG
authors.lastname: Kester
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: Dirk M
authors.initials: DM
authors.lastname: van der Steen
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: Renate S
authors.initials: RS
authors.lastname: Hagedoorn
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: J H Frederik
authors.initials: JH
authors.lastname: Falkenburg
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Peter A
authors.initials: PA
authors.lastname: van Veelen
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: Mirjam H M
authors.initials: MH
authors.lastname: Heemskerk
mesh_terms: D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D051925:CD79 Antigens / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000276:immunology; D015793:HLA-B7 Antigen / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D051925:CD79 Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D015793:HLA-B7 Antigen; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell