The CD47-SIRPα pathway in cancer immune evasion and potential therapeutic implications

Abstract

Multiple lines of investigation have demonstrated that the immune system plays an important role in preventing tumor initiation and controlling tumor growth. Accordingly, many cancers have evolved diverse mechanisms to evade such monitoring. While multiple immune cell types mediate tumor surveillance, recent evidence demonstrates that macrophages, and other phagocytic cells, play a key role in regulating tumor growth through phagocytic clearance. In this review we highlight the role of tumor immune evasion through the inhibition of phagocytosis, specifically through the CD47-signal-regulatory protein-α pathway, and discuss how targeting this pathway might lead to more effective cancer immunotherapies.

Figure 1. Mechanisms of targeting the CD47-SIRPα pathway in cancer

Therapeutic targeting of the CD47-SIRPα pathway can cause elimination of cancer cells through multiple mechanisms. First, inhibition of the CD47-SIRPα interaction with a blocking anti-CD47 antibody, a blocking anti-SIRPα antibody, or a recombinant SIRPα protein (depicted here as a bivalent Fc-fusion protein) leads to phagocytic uptake of tumor cells by macrophages. Second, an anti-CD47 antibody can eliminate tumor cells through traditional antibody Fc-dependent mechanisms including NK cell-mediated ADCC and CDC. Third, anti-CD47 antibody may directly stimulate apoptosis of tumor cells through a caspase-independent mechanism. Fourth, anti-CD47 antibody may enable phagocytic uptake of tumor cells by DCs and subsequent antigen presentation to CD4 and CD8 T cells, thereby stimulating an anti-tumor adapative immune response. mAb=monoclonal antibody.

Figure 2. Combination strategies targeting CD47 in cancer

Anti-CD47 antibody may be utilized in several combination strategies to more effectively target tumor cells. First, anti-CD47 antibody may be combined with a second antibody against a tumor-specific antigen either separately or in a bi-specific format to recruit multiple cytotoxic mechanisms: macrophage-mediated phagocytosis, NK cell mediated-ADCC, and/or CDC. Second, anti-CD47 antibody may be combined with agents that augment macrophage effector cell number and function, including M-CSF or GM-CSF, to increase effector cells at tumor sites to enable phagocytic elimination. Third, chemotherapy and/or radiation may be combined with anti-CD47 antibody to induce pro-phagocytic signals (calreticulin) on tumor cells to augment anti-CD47 antibody potency. Fourth, given the ability of anti-CD47 antibody to inhibit tumor metastasis through phagocytosis by vascular-lining macrophages or direct inhibition of chemotaxis, this therapy can be administered systemically and/or infused locally at the time of surgical excision of the tumor mass to prevent metastatic spread.