1. CD20 expression regulates CD37 levels in B-cell lymphoma - implications for immunotherapies.
- Author
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Bobrowicz M, Kusowska A, Krawczyk M, Zhylko A, Forcados C, Slusarczyk A, Barankiewicz J, Domagala J, Kubacz M, Šmída M, Dostalova L, Marhelava K, Fidyt K, Pepek M, Baranowska I, Szumera-Cieckiewicz A, Inderberg EM, Wälchli S, Granica M, Graczyk-Jarzynka A, Majchrzak M, Poreba M, Gehlert CL, Peipp M, Firczuk M, Prochorec-Sobieszek M, and Winiarska M
- Subjects
- Humans, Cell Line, Tumor, Antigens, Neoplasm immunology, Antigens, Neoplasm genetics, Drug Resistance, Neoplasm drug effects, Antineoplastic Combined Chemotherapy Protocols pharmacology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Doxorubicin pharmacology, Doxorubicin administration & dosage, Cyclophosphamide pharmacology, Cyclophosphamide therapeutic use, Vincristine pharmacology, Vincristine therapeutic use, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal therapeutic use, Receptors, Chimeric Antigen immunology, Receptors, Chimeric Antigen genetics, Receptors, Chimeric Antigen metabolism, Gene Expression Regulation, Neoplastic, Antigens, CD20 immunology, Antigens, CD20 metabolism, Antigens, CD20 genetics, Rituximab pharmacology, Rituximab therapeutic use, Tetraspanins genetics, Tetraspanins metabolism, Lymphoma, B-Cell immunology, Lymphoma, B-Cell therapy, Lymphoma, B-Cell genetics, Lymphoma, B-Cell drug therapy, Immunotherapy methods
- Abstract
Rituximab (RTX) plus chemotherapy (R-CHOP) applied as a first-line therapy for lymphoma leads to a relapse in approximately 40% of the patients. Therefore, novel approaches to treat aggressive lymphomas are being intensively investigated. Several RTX-resistant (RR) cell lines have been established as surrogate models to study resistance to R-CHOP. Our study reveals that RR cells are characterized by a major downregulation of CD37, a molecule currently explored as a target for immunotherapy. Using CD20 knockout (KO) cell lines, we demonstrate that CD20 and CD37 form a complex, and hypothesize that the presence of CD20 stabilizes CD37 in the cell membrane. Consequently, we observe a diminished cytotoxicity of anti-CD37 monoclonal antibody (mAb) in complement-dependent cytotoxicity in both RR and CD20 KO cells that can be partially restored upon lysosome inhibition. On the other hand, the internalization rate of anti-CD37 mAb in CD20 KO cells is increased when compared to controls, suggesting unhampered efficacy of antibody drug conjugates (ADCs). Importantly, even a major downregulation in CD37 levels does not hamper the efficacy of CD37-directed chimeric antigen receptor (CAR) T cells. In summary, we present here a novel mechanism of CD37 regulation with further implications for the use of anti-CD37 immunotherapies., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)
- Published
- 2024
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