Daratumumab prevents programmed death ligand‐1 expression on antigen‐presenting cells in de novo multiple myeloma

International audienceBackground: Daratumumab (Dara), an anti-CD38 monoclonal antibody, has an immunologic mechanism of action through targeting of CD38 expressing immune cells in patients with multiple myeloma (MM). Furthermore, it was recently shown that CD38 upregulation in tumors, is a major mechanism of acquired resistance to antiprogrammed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1). Therefore, we decided to evaluate the immunomodulatory effects of CD38 blockade by Dara on the PD-L1 expressing immune cells.Methods: We analyzed CD38 and PD-L1 expression on immune cells at different time points in 18 newly diagnosed MM receiving bortezomib, lenalidomide and dexamethasone, with or without Dara.Results: We first confirmed that CD38 is widely expressed on immune cells, with the strongest expression on plasmacytoid dendritic cells (pDC). Furthermore, Dara induces a strong depletion of pDC in addition to the well-known rapid depletion of natural killer cells. Finally, we found that PD-L1 expression on antigen-presenting cells (APC) increases with MM treatment in patients that did not received Dara, while addition of Dara prevents this increase.Conclusion: Overall, our results suggest new mechanisms of action of Dara through depletion of pDC and prevention of PD-L1 upregulation expression on APC. Our finding provides new evidences for development of therapeutic strategies targeting both CD38 and PD-L1/PD-1 pathway in patients with MM

Arsenic trioxide induces regulatory functions of plasmacytoid dendritic cells through interferon-α inhibition

International audienceArsenic trioxide (As 2 O 3) is recently found to have therapeutic potential in systemic sclerosis (SSc), a life-threatening multi-system fibrosing autoimmune disease with type I inter-feron (IFN-I) signature. Chronically activated plasmacytoid dendritic cells (pDCs) are responsible for IFN-I secretion and are closely related with fibrosis establishment in SSc. In this study, we showed that high concentrations of As 2 O 3 induced apoptosis of pDCs via mitochondrial pathway with increased BAX/BCL-2 ratio, while independent of reactive oxygen species generation. Notably, at clinical relevant concentrations, As 2 O 3 preferentially inhibited IFN-a secretion as compared to other cytokines such as TNF-a, probably due to potent down-regulation of the total protein and mRNA expression, as well as phosphorylation of the interferon regulatory factor 7 (IRF7). In addition, As 2 O 3 induced a suppressive phenotype, and in combination with cytokine inhibition, it down-regulated pDCs' capacity to induce CD4 þ T cell proliferation, Th1/Th22 polarization, and B cell differentiation towards plasmablasts. Moreover, chronically activated pDCs from SSc patients were not resistant to the selective IFN-a inhibition, and regulatory phenotype induced by As 2 O 3. Collectively, our data suggest that As 2 O 3 could target pDCs and exert its treatment efficacy in SSc, and more autoimmune disorders with IFN-I signature