1. Academic Validation
  2. Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity

Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity

  • Cancer Cell. 2023 May 23;S1535-6108(23)00142-3. doi: 10.1016/j.ccell.2023.04.016.
Chengsong Yan 1 Lin Zheng 2 Shutan Jiang 2 Haochen Yang 2 Jun Guo 2 Lu-Yi Jiang 3 Tongzhou Li 4 Haosong Zhang 4 Yibing Bai 2 Yu Lou 5 Qi Zhang 5 Tingbo Liang 5 Wolfgang Schamel 6 Haopeng Wang 7 Weiwei Yang 2 Guangchuan Wang 2 Zheng-Jiang Zhu 4 Bao-Liang Song 8 Chenqi Xu 9
Affiliations

Affiliations

  • 1 Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China; State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology; University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 2 State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology; University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 3 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China.
  • 4 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
  • 5 Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 6 Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
  • 7 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 8 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China. Electronic address: blsong@whu.edu.cn.
  • 9 Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China; State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology; University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. Electronic address: cqxu@sibcb.ac.cn.
Abstract

The concept of targeting Cholesterol metabolism to treat Cancer has been widely tested in clinics, but the benefits are modest, calling for a complete understanding of Cholesterol metabolism in intratumoral cells. We analyze the Cholesterol atlas in the tumor microenvironment and find that intratumoral T cells have Cholesterol deficiency, while immunosuppressive myeloid cells and tumor cells display Cholesterol abundance. Low Cholesterol levels inhibit T cell proliferation and cause autophagy-mediated Apoptosis, particularly for cytotoxic T cells. In the tumor microenvironment, oxysterols mediate reciprocal alterations in the LXR and SREBP2 pathways to cause Cholesterol deficiency of T cells, subsequently leading to aberrant metabolic and signaling pathways that drive T cell exhaustion/dysfunction. LXRβ depletion in chimeric antigen receptor T (CAR-T) cells leads to improved antitumor function against solid tumors. Since T cell Cholesterol metabolism and oxysterols are generally linked to Other Diseases, the new mechanism and cholesterol-normalization strategy might have potential applications elsewhere.

Keywords

CAR-T cells; Intratumoral T cells; autophagy-mediated apoptosis; cholesterol deficiency; cholesterol normalization; oxysterols.

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