Immunosuppressive Adenosine - a Novel Treatment Target for Multiple Myeloma

Anti-PD1/PDL1 checkpoint therapy has been unsuccessful in myeloma patients. Adenosine is a new therapeutic target for cancer therapy. Two ectoenzymes, CD39 and CD73, catalyse adenosine from extracellular ATP. CD39 converts ATP to AMP and CD73 AMP to adenosine. When investigating the role of adenosine in the immune response patients, we found increased concentration of adenosine in bone marrow plasma from myeloma patients compared with healthy controls. CD39 was expressed on myeloma cells and immune cells whereas CD73 was found on leukocytes and stromal cells in the bone marrow. Adenosine generated from co-cultures of CD39+ myeloma cells and CD73+ stromal cells reduced the proliferation of T cells stimulated with anti-CD3/CD28 beads which was reversed by inhibitors of the A2ARA adenosine receptor. A CD39 inhibitor, POM-1, and an anti-CD73 antibody inhibited adenosine generation and blockade of T cell proliferation in vitro. Blocking of the adenosine pathway in vivo with a combination of POM-1, anti-CD73, and the A2AR antagonist AZD4635 activated immune cells, increased IFNγ production and reduced the tumor load in a murine model of multiple myeloma. This suggests that the adenosine pathway is involved in immune suppression in multiple myeloma and that this pathway is a potential novel therapeutic target.