1. Targeting metabolic sensing switch GPR84 on macrophages for cancer immunotherapy.
- Author
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Li, Jianying, Ma, Anjun, Zhang, Ruohan, Chen, Yao, Bolyard, Chelsea, Zhao, Bao, Wang, Cankun, Pich, Thera, Li, Wantong, Sun, Nuo, Ma, Qin, Wen, Haitao, Clinton, Steven K., Carson III, William E., Li, Zihai, and Xin, Gang
- Subjects
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MACROPHAGES , *IMMUNE checkpoint proteins , *IMMUNOTHERAPY , *TUMOR growth , *T cells - Abstract
Introduction: As one of the major components of the tumor microenvironment, tumor-associated macrophages (TAMs) possess profound inhibitory activity against T cells and facilitate tumor escape from immune checkpoint blockade therapy. Converting this pro-tumorigenic toward the anti-tumorigenic phenotype thus is an important strategy for enhancing adaptive immunity against cancer. However, a plethora of mechanisms have been described for pro-tumorigenic differentiation in cancer, metabolic switches to program the anti-tumorigenic property of TAMs are elusive. Materials and methods: From an unbiased analysis of single-cell transcriptome data from multiple tumor models, we discovered that anti-tumorigenic TAMs uniquely express elevated levels of a specific fatty acid receptor, G-protein-coupled receptor 84 (GPR84). Genetic ablation of GPR84 in mice leads to impaired pro-inflammatory polarization of macrophages, while enhancing their anti-inflammatory phenotype. By contrast, GPR84 activation by its agonist, 6-n-octylaminouracil (6-OAU), potentiates pro-inflammatory phenotype via the enhanced STAT1 pathway. Moreover, 6-OAU treatment significantly retards tumor growth and increases the anti-tumor efficacy of anti-PD-1 therapy. Conclusion: Overall, we report a previously unappreciated fatty acid receptor, GPR84, that serves as an important metabolic sensing switch for orchestrating anti-tumorigenic macrophage polarization. Pharmacological agonists of GPR84 hold promise to reshape and reverse the immunosuppressive TME, and thereby restore responsiveness of cancer to overcome resistance to immune checkpoint blockade. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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