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

Abstract

Background 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.

Monoclonal Antibodies and Antibody Drug Conjugates in Multiple Myeloma

“…Other immune effector cells also show high expression of CD38 including regulatory B cells and antigen presenting cells (APC), especially plasmacytoid dendritic cells. A decrease in plasmacytoid densdritic cells, which support MM cell growth and survival, may represent another potent immune effect of CD38 antibodies [ 5 , 6 ]. CD38 works as an enzyme (ectoenzyme) at it also can serve as a receptor triggering proliferation signals [ 7 ].…”

Landscape of coordinated immune responses to H1N1 challenge in humans

“…Interestingly, a study detailing acute Ebola infection of humans similarly found that CD38 upregulation on pDCs was correlated to declining viral load (48), suggesting that pDC CD38's role in viral infections may be broader than just influenza. The relevance of CD38 on pDCs is further underscored by a report that the CD38-targeted therapeutic daratumumab (63), approved for the treatment of multiple myeloma, depletes circulating pDCs (64). Strategies for the modulation of pDC CD38 may warrant investigation as potential therapies for viral infections or autoimmune diseases associated with dysregulated overaction of pDC IFN-I production.…”

PD-L1/PD-1 Axis in Multiple Myeloma Microenvironment and a Possible Link with CD38-Mediated Immune-Suppression

“…CD38/ADO and PD-1/PD-L1 axis in cancers; however, this approach has not been explored in depth in MM patients. Interestingly, it has been reported that the treatment with anti-CD38 mAb daratumumab (DARA) prevents the increase of PD-L1 expression on antigen presenting cells induced by the standard treatment without DARA in MM patients [95]. Moreover, it has been showed that MM cells increase PD-1 expression by NK and PD-L1 by monocytes and that PD-1/PD-L1 axis suppress the antibody-dependent cellular cytotoxicity (ADCC) mediated by the anti-CD38 mAb isatuximab [96].…”