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

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.

The roles of cellular protease interactions in viral infections and programmed cell death: a lesson learned from the SARS-CoV-2 outbreak and COVID-19 pandemic.

The unprecedented pandemic of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), which leads to COVID-19, is threatening global health. Over the last 2 years, we have witnessed rapid progress in research focusing on developing new antiviral vaccines and drugs, as well as in academic and clinical efforts to understand the biology and pathology of COVID-19. The roles of proteases among master regulators of SARS-CoV-2 invasion and replication and their pivotal roles in host defence against this pathogen, including programmed cell death, have not been well established. Our understanding of protease function in health and disease has increased considerably over the last two decades, with caspases, matrix metalloproteases, and transmembrane serine proteases representing the most prominent examples. Therefore, during the COVID-19 pandemic, these enzymes have been investigated as potential molecular targets for therapeutic interventions. Proteases that are responsible for SARS-CoV-2 cell entry and replication, such as TMPRSS2, ACE2 or cathepsins, are screened with inhibitor libraries to discover lead structures for further drug design that would prevent virus multiplication. On the other hand, proteases that orchestrate programmed cell death can also be harnessed to enhance the desired demise of infected cells through apoptosis or to attenuate highly inflammatory lytic cell death that leads to undesired cytokine storms, a major hallmark of severe COVID-19. Given the prominent role of proteases in SARS-CoV-2-induced cell death, we discuss the individual roles of these enzymes and their catalytic interactions in the pathology of COVID-19 in this article. We provide a rationale for targeting proteases participating in cell death as potential COVID-19 treatments and identify knowledge gaps that might be investigated to better understand the mechanism underlying SARS-CoV-2-induced cell death.