Lu Siyuan, Chen Xuezhu, Yang Yang, Li Junlong
Office of Scientific Research Administration, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
Department of Radiology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, Jiangsu, China.
Heliyon. 2024 Nov 28;10(23):e40806. doi: 10.1016/j.heliyon.2024.e40806. eCollection 2024 Dec 15.
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.
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.
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.
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.
大麻素给药已通过抑制胶质瘤细胞增殖和诱导胶质瘤细胞死亡，展现出对胶质母细胞瘤（GBM）有前景的抗肿瘤作用。然而，大麻素和内源性大麻素受体对肿瘤微环境（TME）中免疫细胞的影响在很大程度上仍未被探索。肿瘤相关巨噬细胞（TAM）是TME中最丰富的免疫细胞，其介导的肿瘤细胞吞噬作用在各种人类恶性肿瘤的临床前异种移植中已显示出潜力。本研究旨在探讨内源性大麻素受体2（CB2R）对GL261 - GFP细胞系异种移植小鼠中TAM介导的吞噬作用的影响及机制。
我们使用免疫荧光和流式细胞术测量吞噬活性，并使用IVIS Spectrum系统进行生物发光成像以追踪肿瘤生长。
我们的研究结果表明，给予选择性CB2R激动剂JWH133可显著增强TAM介导的吞噬作用。然而，给予选择性CB2R拮抗剂AM630可显著抑制TAM介导的吞噬作用。机制上，CB2R激活上调了TAM上CD36的表达，CD36是一种已知可促进吞噬作用的清道夫受体。此外，不可逆的CD36抑制剂磺基 - N - 琥珀酰亚胺油酸酯（SSO）可逆转CB2R激活诱导的TAM吞噬作用增强。此外，JHW133还有效增强了替莫唑胺的化疗疗效。
总体而言，我们的研究结果表明，CB2R激活通过增强CD36表达促进TAM介导的肿瘤细胞吞噬作用，这意味着JWH133可能是提高对GBM化疗疗效的一种有用治疗方法。
