Phagocytosis Checkpoints in Glioblastoma: CD47 and Beyond

Abstract

Glioblastoma multiforme (GBM) is one of the deadliest human cancers with very limited treatment options available. The malignant behavior of GBM is manifested in a tumor which is highly invasive, resistant to standard cytotoxic chemotherapy, and strongly immunosuppressive. Immune checkpoint inhibitors have recently been introduced in the clinic and have yielded promising results in certain cancers. GBM, however, is largely refractory to these treatments. The immune checkpoint CD47 has recently gained attention as a potential target for intervention as it conveys a "don't eat me" signal to tumor-associated macrophages (TAMs) via the inhibitory SIRP alpha protein. In preclinical models, the administration of anti-CD47 monoclonal antibodies has shown impressive results with GBM and other tumor models. Several well-characterized oncogenic pathways have recently been shown to regulate CD47 expression in GBM cells and glioma stem cells (GSCs) including Epidermal Growth Factor Receptor (EGFR) beta catenin. Other macrophage pathways involved in regulating phagocytosis including TREM2 and glycan binding proteins are discussed as well. Finally, chimeric antigen receptor macrophages (CAR-Ms) could be leveraged for greatly enhancing the phagocytosis of GBM and repolarization of the microenvironment in general. Here, we comprehensively review the mechanisms that regulate the macrophage phagocytosis of GBM cells.

Keywords: CD47; CSF-1R; glioblastoma; glioma; macrophage; phagocytosis; siglec.

Figure 1

Phagocytosis checkpoints at the glioma/macrophage interface. CD47 exhibits bidirectional signaling that promotes both GBM tumor invasion and inhibition of phagocytosis by engaging SIRP receptors on the surface of TAMs. Pathways which regulate CD47 expression include EGFR/SRC, LRIG2, and NF-κB. TREM2 can also promote phagocytosis, while siglecs tend to be strongly immunosuppressive and represent another phagocytosis checkpoint along with CD47. Effective therapy for GBM will likely involve a combination of treatments which induce GBM cell death, promote an immunologically “hot” tumor by activating M1 macrophage pathways and stimulation of GBM phagocytosis by TAMs using checkpoint inhibitors.