Author:
Bobrowicz Malgorzata,Kusowska Aleksandra,Krawczyk Marta,Slusarczyk Aleksander,Barankiewicz Joanna,Domagala Joanna,Kubacz Matylda,Šmída Michal,Dostalova Lenka,Marhelava Katsiaryna,Fidyt Klaudyna,Forcados Christopher,Pepek Monika,Baranowska Iwona,Szumera-Cieckiewicz Anna,Inderberg Else Marit,Wälchli Sébastien,Graczyk-Jarzynka Agnieszka,Gehlert Carina Lynn,Peipp Matthias,Firczuk Malgorzata,Prochorec-Sobieszek Monika,Winiarska Magdalena
Abstract
AbstractRituximab (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.
Publisher
Cold Spring Harbor Laboratory