CD73 Inhibition Overcomes Immunosuppression and Triggers Autologous T-Cell Mediated Multiple Myeloma Cell Lysis in the Bone Marrow Milieu

Introduction: Adenosine is an anti-inflammatory and immunosuppressive metabolite, that signals to diminish activation and proliferation of cytotoxic T-cells, impair activity of natural killer cells and CD4 + effector T-cells, and promote the expansion of immunosuppressive cell types. CD73, a cell surface ecto-5'-nucleotidase, is required to convert AMP to adenosine and is a major catalyst of adenosine generation in the tumor microenvironment. Overexpression of CD73 is observed in many tumors and correlates with unfavorable clinical outcome. Bone marrow (BM) aspirates from multiple myeloma (MM) patients have shown increased adenosine levels correspond with disease progression [Horenstein et al. Mol Med. 2016,22:694-704] In addition to the adenosine rich feature of MM, multiple cell types within the MM BM niche express the enzymes required for adenosine production from both NAD and ATP precursors, including CD38, CD203a, CD39 and CD73. Previously, we demonstrated that dysfunctional plasmacytoid dendritic cells (pDCs) predominantly found in the BM of MM patients contribute to MM cell growth, survival, and suppression of antitumor immunity [Chauhan et al, Cancer Cell 2009, 16:309-323; Ray et al, Leukemia 2015, 29:1441-1444]. We recently discovered that the interaction between pDCs and MM cells increased CD73 transcript and protein levels in both cell types, implicating a role for adenosine signaling via CD73 signaling axis in MM. Together, these MM disease features indicate that reducing the level of adenosine via inhibition of CD73 may represent a unique vulnerability and treatment strategy for MM.