Abstract LB-117: Role of ectoenzymes CD39 and CD73 in the immune response to multiple myeloma

Abstract

Abstract Multiple Myeloma is a cancer of the plasma cells in the bone marrow. Despite from the fact that new drugs have increased survival in the past decade, it is still an incurable cancer. It is therefore important to develop new drugs. Tumor immunosurveillance contributes to the control of cancer growth, but there many different escape mechanisms utilized by tumour to evade anti-tumour immune responses. One of the largely unexplored mechanisms of immune suppression in multiple myeloma is the role of adenosine in the bone marrow microenvironment, which now represents an attractive new therapeutic target for cancer therapy. 2 ectoenzymes, CD39 and CD73 are important for converting extracellular ATP to adenosine. When investigating the role of adenosine in the immune response to multiple myeloma, we found increased concentration of adenosine in the bone marrow plasma from myeloma patients compared with healthy controls. CD39 (ENTPD1) was expressed by myeloma cell lines and on myeloma cells from patients. CD73 was found on leukocytes and stromal cells in the bone marrow. Although very few cells expressed CD73 in the bone marrow, these cells could clearly convert AMP to adenosine. ATP was converted to AMP by CD39+ myeloma cell lines, and CD73+ stromal cells converted AMP to adenosine. Importantly, co-culture of CD39+ myeloma cells and CD73+ stromal cells catalyzed extracellular ATP to immunosuppressive adenosine. Indeed, we found that CD3 T cells stimulated with anti CD3/CD28 beads in the presence of supernatants from co-cultured cells did not proliferate as well as T cell culture without this supernatant. The fact that this proliferation was inhibited by the ZM241385 inhibitor, suggested that the suppression was mediated by the A2AR receptor. The CD39 inhibitor POM1 inhibited adenosine generation in the co-culture system as well as T cell proliferation in vitro. We have recently obtained the CD73 antibody MEDI199447 from MedImmune and are testing the ability of this antibody to prevent adenosine production and T cell proliferation in vitro, as well as the ability to reduce tumor growth in a mouse model of multiple myeloma. The clinical importance of the adenosine pathway in multiple myeloma found when analyzing patient data. Using the publicly available coMMpass database, we found that patients with high expression of CD39 had significantly reduced progression free and overall survival. Citation Format: Rui Yang, Samah Elsaadi, Kristine Misund, Geir Slupphaug, Eline Menu, Carl Hay, Zac Cooper, Karin Vanderkerken, Magne Børset, Anne Marit Sponaas. Role of ectoenzymes CD39 and CD73 in the immune response to multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-117.