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

SIMPLE SUMMARY: Despite the impressive clinical impact of programmed death-ligand 1 (PD-L1)/programmed cell death-1 (PD-1) blockade in solid tumors, the use of these checkpoint inhibitors in multiple myeloma (MM) still remains debated with unsatisfying clinically meaningful results. In this review we summarize the available literature data on the PD-L1/PD-1 expression profile, highlighting some discrepancies and providing a rationale for the combination with anti-CD38 antibodies, in light of the immunosuppressive effect of CD38-mediated adenosine production. ABSTRACT: The emerging role of the PD-1/PD-L1 axis in MM immune-microenvironment has been highlighted by several studies. However, discordant data have been reported on PD-1/PD-L1 distribution within the bone marrow (BM) microenvironment of patients with monoclonal gammopathies. In addition, the efficacy of PD-1/PD-L1 blockade as a therapeutic strategy to reverse myeloma immune suppression and inhibit myeloma cell survival still remains unknown. Recent data suggest that, among the potential mechanisms behind the lack of responsiveness or resistance to anti-PD-L1/PD-1 antibodies, the CD38 metabolic pathways involving the immune-suppressive factor, adenosine, could play an important role. This review summarizes the available data on PD-1/PD-L1 expression in patients with MM, reporting the main mechanisms of regulation of PD-1/PD-L1 axis. The possible link between the CD38 and PD-1/PD-L1 pathways is also reported, highlighting the rationale for the potential use of a combined therapeutic approach with CD38 blocking agents and anti-PD-1/PD-L1 antibodies in order to improve their anti-tumoral effect in MM patients.