The CD47‐SIRPα signaling axis as an innate immune checkpoint in cancer

Abstract

Immune checkpoint inhibitors, including those targeting CTLA-4/B7 and the PD-1/PD-L1 inhibitory pathways, are now available for clinical use in cancer patients, with other interesting checkpoint inhibitors being currently in development. Most of these have the purpose to promote adaptive T cell-mediated immunity against cancer. Here, we review another checkpoint acting to potentiate the activity of innate immune cells towards cancer. This innate immune checkpoint is composed of what has become known as the 'don't-eat me' signal CD47, which is a protein broadly expressed on normal cells and often overexpressed on cancer cells, and its counter-receptor, the myeloid inhibitory immunoreceptor SIRPα. Blocking CD47-SIRPα interactions has been shown to promote the destruction of cancer cells by phagocytes, including macrophages and neutrophils. Furthermore, there is growing evidence that targeting of the CD47-SIRPα axis may also promote antigen-presenting cell function and thereby stimulate adaptive T cell-mediated anti-cancer immunity. The development of CD47-SIRPα checkpoint inhibitors and the potential side effects that these may have are discussed. Collectively, this identifies the CD47-SIRPα axis as a promising innate immune checkpoint in cancer, and with data of the first clinical studies with CD47-SIRPα checkpoint inhibitors expected within the coming years, this is an exciting and rapidly developing field.

Mithramycin-loaded mPEG-PLGA nanoparticles exert potent antitumor efficacy against pancreatic carcinoma

“…Notably, the treatment of MIT-NPs reduced Figure 6A), a membrane protein that took part in innate immune checkpoint in cancer. 32 In tumor tissue of the MIT-NPs group (2 mg/kg), a more striking number of vacuoles existed as compared with that of the control group. These vacuoles appeared in blue with AB mucin staining ( Figure 6B), indicating that acidic glycan occurs in the vacuole structure.…”

“…It plays a significant role in the innate immune checkpoint through interaction with signal regulatory protein-α (SIRPα), a myeloid inhibitory immunoreceptor. 32 A previous study had suggested that CD47 was highly expressed on primary pancreatic cancer cells and the anti-CD47 monoclonal antibodies (mAbs) could enable phagocytosis of cancer cells by macrophages as well as inhibit self-renewal of cancer stem cells. 38 In comparison to the relatively stable expression of SIRPα, the variable levels of CD47 may be relevant to immune checkpoint in cancer.…”

“…38 In comparison to the relatively stable expression of SIRPα, the variable levels of CD47 may be relevant to immune checkpoint in cancer. 32 Several clinical studies have shown the expression level of CD47 in tumor tissues to be positively correlated with the resistance to both chemotherapy and antibody therapy. 32,39 Furthermore, the decreased level of CD47 may change tumor microenvironment via interaction with thrombospondin-1 (TSP-1), which is overexpressed in the tumor stroma and takes part in the regulation of angiogenesis and inflammation.…”

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

“…The intended/expected activity of both classes of therapeutics is to enhance phagocytic clearance of tumor cells by macrophages by inhibiting the CD47-SIRPa interaction (157), but understanding the role of CD47 in redox signaling can illuminate potential side effects of these therapeutics.…”

“…Therapeutic applications for cancer. The abnormal vasculature of tumors tends to be unresponsive to NO (88), but the ability of CD47 blockade to modulate responses to radiation and redox signaling involved in innate and adaptive antitumor immunity provides therapeutic opportunities for improving the activities of both conventional cytotoxic therapies and immunotherapy of cancer (134,147,157,248). Several companies are developing biologics targeting CD47 that are designed to inhibit its interactions with SIRPa, and several of these have entered human clinical trials for cancer patients (NCT02216409, NCT02678338, NCT02953509, NCT02953782, NCT02367196, NCT02488811, and NCT02641002).…”