2. Academic Validation
  3. Myeloid-derived suppressor cells deficient in cholesterol biosynthesis promote tumor immune evasion

Myeloid-derived suppressor cells deficient in cholesterol biosynthesis promote tumor immune evasion

  • Cancer Lett. 2023 May 5;216208. doi: 10.1016/j.canlet.2023.216208.
Yu Chen 1,  Yanquan Xu 2,  Huakan Zhao 1,  Yu Zhou 1,  Jiangang Zhang 1,  Juan Lei 1,  Lei Wu 1,  Mingyue Zhou 1,  Jingchun Wang 3,  Shuai Yang 4,  Xiao Zhang 5,  Guifang Yan 6,  Yongsheng Li 7
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, 400030, China.
  • 2 Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
  • 3 Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
  • 4 Department of Pathology, The 958th Hospital, Southwest Hospital, Third Military Medical University, Chongqing, 400037, China.
  • 5 Army 953 Hospital, Shigatse Branch of Xinqiao Hospital, Army Medical University, Shigatse, Tibet Autonomous Region, 857000, China.
  • 6 Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, 400030, China. Electronic address: 313504423@qq.com.
  • 7 Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, 400030, China; Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China. Electronic address: lys@cqu.edu.cn.
PMID: 37150500 DOI: 10.1016/j.canlet.2023.216208
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.

Keywords

Cholesterol; Metabolism; Myeloid-derived suppressor cells; Tumor immunity; Tumor microenvironment.

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