CD73 Dysregulates Monocyte Anti-Tumor Activity in Multiple Myeloma.

Abstract

Multiple myeloma (MM) is characterized by immune cell dysfunction in the tumor microenvironment (TME). We aimed at evaluating the effect of CD73, an overexpressed factor in some tumors, on anti-tumor immune function in the TME of MM. We analyzed the expression of CD73 in T-, B-, and natural killer (NK)-lymphocytes and monocytes in bone marrow (BM), peripheral blood (PB) from MM patients and healthy controls, and residual CD138+ cells using flow cytometry. The anti-tumor activity of these monocytes was confirmed by co-culture with RPMI-8226 cells treated with a CD73 inhibitor. We determined the interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ levels using a cytometric bead array. Monocyte phagocytosis in cell culture sediment was then observed and measured. CD73 was highly expressed in T-, B-, and NK-lymphocytes and monocytes from the BM and PB isolated from patients with MM. Compared with healthy controls, MM samples exhibited significantly higher CD73 expression and TNF-α, IFN-γ, IL-10 levels in monocytes. Inhibiting CD73 in BM immune cells from MM samples significantly increased the secretion of IL-2, TNF-α, and IFN-γ, as well as the killing ability of immune cells. However, monocyte phagocytosis was seldom observed. Inhibiting CD73 in MM monocytes significantly increased the secretion of IL-2, TNF-α, and IFN-γ in monocytes and improved monocyte killing and phagocytosis. Monocytes from MM exhibited weakened anti-tumor effects, and CD73 was involved in forming an immunosuppressive microenvironment. Inhibiting CD73 partly restored the anti-tumor activity of monocytes, a potential strategy for the treatment of MM.