Blocking the CD47-SIRPα axis by delivery of anti-CD47 antibody induces antitumor effects in glioma and glioma stem cells

Abstract

Tumor initiating cells or cancer stem cells (CSCs) play an important role in the initiation, development, metastasis, and recurrence of tumors. However, traditional therapies have limited effects against CSCs and targeting these cells is crucial when developing new therapeutic strategies against cancer. One potentially targetable factor is CD47, a member of the immunoglobulin superfamily. This protein acts as an anti-phagocytic "don't eat me" signal and is often found expressed by cancer cells, particularly CSCs. CD47 functions by activating signal regulatory protein-α (SIRP-α) expressed on macrophages, preventing phagocytosis. However, the role of CD47 in glioma stem cells (GSCs) has been not been thoroughly investigated. Our study therefore examined the expression and function of this protein in glioma cells and GSCs. We found that CD47 was highly expressed on glioma cells, especially GSCs, and that expression associated with worse clinical outcomes. We also found that CD47+ glioma cells possessed stem/progenitor cell-like characteristics and knocking down CD47 expression resulted in a reduction in these characteristics. Treatment with anti-CD47 antibody led to increased phagocytosis of glioma cells and GSCs by macrophages. We next examined the effects of anti-CD47 antibody on glioma cells/GSCs in an immune competent mouse glioma model, revealing significant inhibition of tumor growth and prolonged survival times. Importantly, there were no apparent side effects in the animal model. In summary, we have shown that CD47 is a potentially safe and effective therapeutic target for glioma.

Trial watch: chemotherapy-induced immunogenic cell death in immuno-oncology

“…12,19,77,[147][148][149][150] The main advantage of these methods is that they can be employed for both rodent and human cancer cells. In this context, cancer cells potentially undergoing ICD can be examined for the release or exposure of ICD-associated DAMPs (see below), 12,15,21,149,[151][152][153] and/or co-cultured with myeloid cells such as dendritic cells (DCs) 21,119,[154][155][156] which are ultimately assessed for: (1) phagocytic activity, [157][158][159][160][161][162][163][164][165] (2) surface activation markers (e.g. CD80, CD83, CD86, CD83, CD40 and/or MHC Class II molecules), 166 (3) secretory activity, with specific reference to interleukin 1 beta (IL1B), IL6, IL12 and tumor necrosis factor (TNF), [167][168][169][170][171][172] and (4) T-cell crosspriming.…”

Improving the efficacy of osteosarcoma therapy: combining drugs that turn cancer cell ‘don't eat me’ signals off and ‘eat me’ signals on

“…Combination therapy of doxorubicin and CD47 mAb has shown success in different cancers (Feliz-Mosquea et al, 2018;Iribarren et al, 2019;Li et al, 2018;Wu et al, 2018) but their efficacy in osteosarcoma remains unknown. To our knowledge, our study is the first to evaluate the efficacy of combination therapy with doxorubicin in osteosarcomas.…”

“…Therapy of high-grade osteosarcomas includes chemotherapy with doxorubicin, cisplatin, and methotrexate and resection of the primary tumor (Bielack et al, 2002;Link et al, 1986;Marina et al, 2016). Unfortunately, the outcome of patients with metastatic disease remains dismal, with survival rates of 15-30% (Aljubran et al, 2009;Marina et al, 2016).…”

MicroRNA-200a Promotes Phagocytosis of Macrophages and Suppresses Cell Proliferation, Migration, and Invasion in Nasopharyngeal Carcinoma by Targeting CD47

“…Accumulating evidence suggests that cancer cells can impair the immune system and evade phagocytosis by macrophages via the activation of CD47 signaling [6,7]. Indeed, CD47 is considered a fundamental "do not eat me" signal [8][9][10][11], and it negatively regulates phagocytosis by binding to signal regulatory protein alpha (SIRPα) on phagocytic cells [12,13]. The blockade of CD47-SIRPα interactions has been shown to enhance the phagocytic activity of phagocytes, such as macrophages, toward tumor cells, thereby resulting in the efficient eradication of tumor cells [14].…”