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Phagocytosis Checkpoints in Glioblastoma: CD47 and Beyond
Amber Afzal1, Zobia Afzal1, Sophia Bizink1
1School of Integrative Science and Technology, Kean University, Union, NJ 07083, USA.
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.
Insights
Glioblastoma multiforme (GBM) is a deadly cancer resistant to current therapies. Targeting the CD47 immune checkpoint and enhancing macrophage phagocytosis show promise for new GBM treatments.
Area of Science:
- Neuro-oncology
- Immunology
- Cancer Biology
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor prognosis.
- GBM exhibits invasiveness, chemoresistance, and immunosuppression, limiting treatment efficacy.
- Current immunotherapies, like checkpoint inhibitors, are largely ineffective against GBM.
Purpose of the Study:
- To review mechanisms regulating macrophage phagocytosis of GBM cells.
- To explore CD47 as a therapeutic target to overcome GBM's immune evasion.
- To discuss novel strategies like CAR-macrophages for GBM treatment.
Main Methods:
- Review of preclinical studies on anti-CD47 antibodies in GBM models.
- Analysis of oncogenic pathways (EGFR, beta-catenin) regulating CD47 expression in GBM and glioma stem cells (GSCs).
- Discussion of macrophage pathways (TREM2, glycan-binding proteins) and CAR-macrophages.
Main Results:
- Anti-CD47 antibodies demonstrate significant efficacy in preclinical GBM models.
- Oncogenic pathways like EGFR and beta-catenin modulate CD47 expression on GBM cells.
- CAR-macrophages offer potential for enhanced GBM phagocytosis and microenvironment repolarization.
Conclusions:
- Targeting CD47 represents a promising strategy to enhance macrophage-mediated GBM cell clearance.
- Understanding regulators of CD47 expression and macrophage phagocytosis is crucial for developing effective GBM immunotherapies.
- Chimeric antigen receptor macrophages (CAR-Ms) hold potential for improving GBM treatment outcomes.
