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

Bobrowicz, M.; Kusowska, A.; Krawczyk, M.; Slusarczyk, A.; Barankiewicz, J.; Domagala, J.; Kubacz, M.; Smida, M.; Dostalova, L.; Marhelava, K.; Fidyt, K.; Forcados, C.; Pepek, M.; Baranowska, I.; Szumera-Cieckiewicz, A.; Inderberg, E. M.; Walchli, S.; Graczyk-Jarzynka, A.; Gehlert, C. L.; Peipp, M.; Firczuk, M.; Prochorec-Sobieszek, M.; Winiarska, M.

doi:10.1101/2023.12.06.570441

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bioRxiv · 10.1101/2023.12.06.570441

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

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Abstract

Rituximab (RTX) plus chemotherapy (R-CHOP) applied as a first-line therapy for lymphoma leads to a relapse in approximately 40% of 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 with a major downregulation of CD37, a molecule currently explored as a target for immunotherapy. Using CD20 knockout (KO) cell lines, we demonstrate for the first time that CD20 and CD37 form a complex and 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. 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.

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Bobrowicz, M., Kusowska, A., Krawczyk, M., Slusarczyk, A., Barankiewicz, J., Domagala, J., Kubacz, M., Smida, M., Dostalova, L., Marhelava, K., Fidyt, K., Forcados, C., Pepek, M., Baranowska, I., Szumera-Cieckiewicz, A., Inderberg, E. M., Walchli, S., Graczyk-Jarzynka, A., Gehlert, C. L., Peipp, M., Firczuk, M., Prochorec-Sobieszek, M., Winiarska, M.. 2023-12-08. CD20 expression regulates CD37 levels in B-cell lymphoma: implications for immunotherapies.. https://doi.org/10.1101/2023.12.06.570441

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