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.
- 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: [email protected].
- 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: [email protected].
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.