Myeloid-derived suppressor cells deficient in cholesterol biosynthesis promote tumor immune evasion
Yu Chen1, Yanquan Xu2, Huakan Zhao1
1Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, 400030, China.
Abstract:
Cancer immunotherapy targeting myeloid-derived suppressor cells (MDSCs) is one of the most promising anticancer strategies. Metabolic reprogramming is vital for MDSC activation, however, the regulatory mechanisms of cholesterol metabolic reprogramming in MDSCs remains largely unexplored. Using the receptor-interacting protein kinase 3 (RIPK3)-deficient MDSC model, a previously established tumor-infiltrating MDSC-like model, we found that the cholesterol accumulation was significantly decreased in these cells. Moreover, the phosphorylated AKT-mTORC1 signaling was reduced, and downstream SREBP2-HMGCR-mediated cholesterol synthesis was blunted. Interestingly, cholesterol deficiency profoundly elevated the immunosuppressive activity of MDSCs. Mechanistically, cholesterol elimination induced nuclear accumulation of LXRβ, thereby promoting LXRβ-RXRα heterodimer binding of a novel composite element in the promoter of Arg1. Furthermore, itraconazole enhanced the immunosuppressive activity of MDSCs to boost tumor growth by suppressing the RIPK3-AKT-mTORC1 pathway and impeding cholesterol synthesis. Our findings demonstrate that RIPK3 deficiency leads to cholesterol abrogation in MDSCs, which facilitates tumor-infiltrating MDSC activation, and highlight the therapeutic potential of targeting cholesterol synthesis to overcome tumor immune evasion.
Insights
Targeting cholesterol metabolism in myeloid-derived suppressor cells (MDSCs) offers a novel cancer immunotherapy approach. RIPK3 deficiency reduces cholesterol, enhancing MDSC immunosuppression and tumor growth, suggesting cholesterol synthesis as a therapeutic target.
Area of Science:
- Immunology
- Cancer Biology
- Metabolic Pathways
Background:
- Myeloid-derived suppressor cells (MDSCs) are crucial regulators of the tumor immune microenvironment.
- Metabolic reprogramming is essential for MDSC function, but cholesterol metabolism in MDSCs is poorly understood.
- Targeting MDSCs is a promising strategy in cancer immunotherapy.
Purpose of the Study:
- To investigate the role of cholesterol metabolism in MDSC function.
- To elucidate the regulatory mechanisms of cholesterol reprogramming in MDSCs.
- To explore the therapeutic potential of targeting cholesterol synthesis in cancer immunotherapy.
Main Methods:
- Utilized a receptor-interacting protein kinase 3 (RIPK3)-deficient MDSC model.
- Analyzed cholesterol accumulation, AKT-mTORC1 signaling, and SREBP2-HMGCR pathway.
- Investigated the impact of cholesterol deficiency on MDSC immunosuppressive activity.
- Examined the role of LXRβ-RXRα heterodimer in Arg1 gene regulation.
- Assessed the effect of itraconazole on MDSC function and tumor growth.
Main Results:
- RIPK3 deficiency led to decreased cholesterol accumulation in MDSCs.
- Phosphorylated AKT-mTORC1 signaling and downstream cholesterol synthesis were reduced.
- Cholesterol deficiency significantly enhanced MDSC immunosuppressive activity.
- Cholesterol elimination promoted LXRβ nuclear accumulation, enhancing Arg1 promoter activity.
- Itraconazole treatment boosted MDSC immunosuppression and tumor growth by inhibiting the RIPK3-AKT-mTORC1 pathway and cholesterol synthesis.
Conclusions:
- RIPK3 deficiency abrogates cholesterol in MDSCs, promoting their immunosuppressive function and tumor growth.
- Targeting cholesterol synthesis in MDSCs represents a potential therapeutic strategy to enhance cancer immunotherapy and overcome immune evasion.
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