In the study published in Immunity, researchers led by Prof. WANG Hongyan from the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences, together with the research group of WEI Bin from Shanghai University, the research group of TANG Huiru from Fudan University and the research group of YE Youqiong from Shanghai Jiao Tong University have identified the role of cholesterol-25-hydroxylase (CH25H) and its metabolite 25-hydroxycholesterol (25HC) in tumor-associated macrophages (TAMs) and suggested CH25H as a novel drug target for tumor immunotherapy.
In response to pathogen infection, macrophages can secrete pro-inflammatory cytokines and interferons to eliminate pathogens. When exposed to the tumor microenvironment, macrophages can also express anti-inflammatory cytokines and arginase (Arg1) to inhibit T cell proliferation and effector function. Cholesterol metabolites are important components of cell membrane and organelle membrane, which can regulate cell proliferation, migration and inflammation. Cholesterol disorders are associated with a variety of diseases.
Researchers have found that 7-dehydrocholesterol (7DHC) accumulation can promote the production of type I interferon to enhance the host against viral infections. The enzyme DHCR7 converts 7DHC into cholesterol, and CH25H could convert cholesterol to 25HC. 25HC has been previously identified as an interferon (IFN)-stimulated gene (ISG), which could block viral entry into the host cells. However, it is remained unclear how 25HC regulates TAMs function and the development of tumor.
The expression levels of cholesterol metabolic enzymes were screened by using three types of immunosuppressive macrophages, including IL-4 and IL-13-stimulated M2 macrophages, macrophages incubated with the cell culture medium from hepatocellular carcinoma cell line Hepa1-6, and TAMs sorted from solid tumors. The expression of CH25H was significantly upregulated. In consistently, the elevated levels of 25HC were found in M2 macrophages, TAMs, and tumors. Researchers analyzed the scRNA-seq data from others' published articles and found that CH25H was highly expressed in MARCO+ TAMs or LYVE1+ TAMs and was negatively correlated with the outcome of tumor patients. CH25H expression was induced by lactate or by IL-4/IL-13 via the transcription factor STAT6.
Mechanically, 25HC accumulates at lysosome and competes with cholesterol for binding to the lysosome-localized protein GPR155 to inhibit mTORC1 activation. AMPKa is then activated to phosphorylate the transcription factor STAT6 at Ser564 to enhance STAT6 transcriptional activity. This leads to the enhanced production of Arg1 and anti-inflammatory factors. Knockout of CH25H in macrophages can reverse the immunosuppressive function of TAM and block the development of tumors, accompanied by the enhanced T cell infiltration and activation with the increased PD-1 levels. Therefore, combination of anti-PD1 antibodies can further enhance the anti-tumor effect.
In summary, targeting CH25H promotes "cold tumor" switching to "hot tumor" that further improve the anti-tumor efficacy together with anti-PD1 therapy.
Contact: hongyanwang@sibcb.ac.cn
Reference: https://doi.org/10.1016/j.immuni.2024.03.021
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