Targeting the CD47-SIRPα Innate Immune Checkpoint to Potentiate Antibody Therapy in Cancer by Neutrophils

SIMPLE SUMMARY: Immunotherapy aims to engage various immune cells in the elimination of cancer cells. Neutrophils are the most abundant leukocytes in the circulation and have unique mechanisms by which they can kill cancer cells opsonized by antibodies. However, neutrophil effector functions are limited by the inhibitory receptor SIRPα, when it interacts with CD47. The CD47 protein is expressed on all cells in the body and acts as a ‘don’t eat me’ signal to prevent tissue damage. Cancer cells can express high levels of CD47 to circumvent tumor elimination. Thus, blocking the interaction between CD47 and SIRPα may enhance anti-tumor effects by neutrophils in the presence of tumor-targeting monoclonal antibodies. In this review, we discuss CD47-SIRPα as an innate immune checkpoint on neutrophils and explore the preliminary results of clinical trials using CD47-SIRPα blocking agents. ABSTRACT: In the past 25 years, a considerable number of therapeutic monoclonal antibodies (mAb) against a variety of tumor-associated antigens (TAA) have become available for the targeted treatment of hematologic and solid cancers. Such antibodies opsonize cancer cells and can trigger cytotoxic responses mediated by Fc-receptor expressing immune cells in the tumor microenvironment (TME). Although frequently ignored, neutrophils, which are abundantly present in the circulation and many cancers, have demonstrated to constitute bona fide effector cells for antibody-mediated tumor elimination in vivo. It has now also been established that neutrophils exert a unique mechanism of cytotoxicity towards antibody-opsonized tumor cells, known as trogoptosis, which involves Fc-receptor (FcR)-mediated trogocytosis of cancer cell plasma membrane leading to a lytic/necrotic type of cell death. However, neutrophils prominently express the myeloid inhibitory receptor SIRPα, which upon interaction with the ‘don’t eat me’ signal CD47 on cancer cells, limits cytotoxicity, forming a mechanism of resistance towards anti-cancer antibody therapeutics. In fact, tumor cells often overexpress CD47, thereby even more strongly restricting neutrophil-mediated tumor killing. Blocking the CD47-SIRPα interaction may therefore potentiate neutrophil-mediated antibody-dependent cellular cytotoxicity (ADCC) towards cancer cells, and various inhibitors of the CD47-SIRPα axis are now in clinical studies. Here, we review the role of neutrophils in antibody therapy in cancer and their regulation by the CD47-SIRPα innate immune checkpoint. Moreover, initial results of CD47-SIRPα blockade in clinical trials are discussed.