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Published on: October 20, 2016
CB2R activation enhances tumor-associated macrophages-mediated phagocytosis of glioma cell
Siyuan Lu1,2, Xuezhu Chen3, Yang Yang4
1Office of Scientific Research Administration, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
Background:
Cannabinoid administration has demonstrated promising anti-tumor effects for glioblastoma (GBM) by inhibiting glioma cell proliferation and inducing glioma cell death. However, the impact of cannabinoids and endocannabinoid receptors on immune cells within the tumor microenvironment (TME) remains largely unexplored. Tumor-associated macrophages (TAMs), the most abundant immune cells in the TME, and their mediated phagocytosis of tumor cells have shown potential in preclinical xenografts of various human malignancies. This study aimed to investigate the effect and mechanism of endocannabinoid receptor 2 (CB2R) on TAMs-mediated phagocytosis in xenografted mice with GL261-GFP cell lines.
Methods:
We measured the phagocytic activity using immunofluorescence and flow cytometry, and we used the IVIS Spectrum System for bioluminescent imaging to track the growth of the tumor.
Results:
Our findings demonstrated that administering JWH133, a selective CB2R agonist, significantly boosted TAMs-mediated phagocytosis. However, administering AM630, a selective CB2R antagonist, significantly inhibited TAMs-mediated phagocytosis. Mechanistically, CB2R activation upregulated the expression of CD36 on TAMs, a scavenger receptor known to facilitate phagocytosis. Furthermore, sulfo-N-succinimidyl oleate (SSO), an irreversible CD36 inhibitor, could reverse the CB2R activation-induced enhancement of phagocytosis by TAMs. Additionally. JHW133 also effectively augmented the chemotherapeutic efficacy of temozolomide.
Conclusion:
Overall, our findings show that CB2R activation promotes TAMs-mediated phagocytosis of tumor cells by enhancing CD36 expression, implying that JWH133 could be a useful therapeutic approach to improving chemotherapeutic efficacy against GBM.
Insights
Cannabinoid receptor 2 (CB2R) activation boosts glioblastoma (GBM) tumor cell destruction by enhancing immune cell phagocytosis. This mechanism involves upregulating CD36 expression on tumor-associated macrophages (TAMs), improving chemotherapy efficacy.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Cannabinoids show anti-tumor effects in glioblastoma (GBM), but their impact on the tumor microenvironment (TME) immune cells is unclear.
- Tumor-associated macrophages (TAMs) are key immune cells in the TME, with phagocytosis potential against tumor cells.
- This study investigates the role of cannabinoid receptor 2 (CB2R) in TAMs-mediated phagocytosis within GBM.
Purpose of the Study:
- To determine the effect of CB2R modulation on TAMs-mediated phagocytosis in a GBM xenograft model.
- To elucidate the underlying mechanism of CB2R's influence on phagocytosis.
- To assess the combined efficacy of CB2R activation and chemotherapy.
Main Methods:
- Utilized GL261-GFP cell lines in xenografted mice.
- Measured phagocytic activity via immunofluorescence and flow cytometry.
- Tracked tumor growth using bioluminescent imaging (IVIS Spectrum System).
Main Results:
- Selective CB2R agonist (JWH133) significantly enhanced TAMs-mediated phagocytosis.
- Selective CB2R antagonist (AM630) significantly inhibited phagocytosis.
- CB2R activation upregulated CD36 expression on TAMs, crucial for phagocytosis, which was reversed by a CD36 inhibitor (SSO).
- JWH133 also improved the efficacy of temozolomide chemotherapy.
Conclusions:
- CB2R activation promotes TAMs-mediated phagocytosis of GBM cells by upregulating CD36 expression.
- JWH133 represents a potential therapeutic strategy to enhance GBM chemotherapeutic efficacy.
