CD20 expression regulates CD37 levels in B-cell lymphoma - implications for immunotherapies

Oncoimmunology. 2024 Jun 4;13(1):2362454. doi: 10.1080/2162402X.2024.2362454. eCollection 2024.

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.

Keywords: B-cell lymphoma; CAR T-cells; CD20; CD37; immunotherapy; rituximab.

MeSH terms

  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use
  • Antigens, CD20* / genetics
  • Antigens, CD20* / immunology
  • Antigens, CD20* / metabolism
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / immunology
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cell Line, Tumor
  • Cyclophosphamide / pharmacology
  • Cyclophosphamide / therapeutic use
  • Doxorubicin / administration & dosage
  • Doxorubicin / pharmacology
  • Drug Resistance, Neoplasm / drug effects
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunotherapy* / methods
  • Lymphoma, B-Cell* / drug therapy
  • Lymphoma, B-Cell* / genetics
  • Lymphoma, B-Cell* / immunology
  • Lymphoma, B-Cell* / therapy
  • Receptors, Chimeric Antigen / genetics
  • Receptors, Chimeric Antigen / immunology
  • Receptors, Chimeric Antigen / metabolism
  • Rituximab* / pharmacology
  • Rituximab* / therapeutic use
  • Tetraspanins* / genetics
  • Tetraspanins* / metabolism
  • Vincristine / pharmacology
  • Vincristine / therapeutic use

Substances

  • Antigens, CD20
  • CD37 protein, human
  • Rituximab
  • Tetraspanins
  • Antigens, Neoplasm
  • Doxorubicin
  • Cyclophosphamide
  • Vincristine
  • Antibodies, Monoclonal
  • Receptors, Chimeric Antigen

Grants and funding

This work was supported by Polish National Science Centre 2019/35/D/NZ5/01191 (MB), Polish National Science Centre 2022/45/N/NZ6/01691 (AK), National Centre for Research and Development within POLNOR program NOR/POLNOR/ALTERCAR/0056/2019 (PI: Magdalena Winiarska), a research grant MUNI/A/1558/2023 (MŠ) and by the project National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102) - Funded by the European Union - Next Generation EU (MŠ). SW and EMI were partially supported by Barnkreftforeningen (PERCAP), KLINBEFORSK (#AML-CD37/2022) and NFR KSP-2021 CellFit project (326811). MP and MM are supported by the NCN grant (2020/39/I/NZ5/03104).