2. Academic Validation
  3. 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.
PMID: 37244259 DOI: 10.1016/j.ccell.2023.04.016
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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