Targeting the CD47-SIRPalpha checkpoint in multiple myeloma.

Immune evasion is a hallmark of cancer and there is mounting evidence that the tumor microenvironment (TME) plays a role in the pathogenesis of haematologic malignancies as well as treatment resistance. Macrophages play a central role in anti-tumor immunity, and dysregulation of macrophage mediated phagocytosis has recently emerged as a key player in blood cancers. The integrin associated protein CD47 is expressed in a variety of cancers and interacts with its ligand, signal regulatory protein α (SIRPα) expressed on macrophages, resulting in down regulation of macrophage-mediated phagocytosis. CD47 is highly expressed in various cancers including multiple myeloma (MM). It is therefore postulated that blockade of the CD47-SIRPα immune checkpoint has the potential to 're-awaken' macrophage mediated phagocytosis of MM plasma cells. In this review, we provide our perspective on the key pre-clinical data supporting the CD47-SIRPα axis as a therapeutic target in MM. We subsequently discuss the ongoing clinical trials which may provide the basis for future clinical translation of these agents. We also highlight key gaps in our knowledge of macrophage biology in MM which need to be addressed by future research. Finally, we present potential future directions for translational research and personalized application of macrophage-based immunotherapy in MM.