1. Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity.
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Yan, Chengsong, Zheng, Lin, Jiang, Shutan, Yang, Haochen, Guo, Jun, Jiang, Lu-yi, Li, Tongzhou, Zhang, Haosong, Bai, Yibing, Lou, Yu, Zhang, Qi, Liang, Tingbo, Schamel, Wolfgang, Wang, Haopeng, Yang, Weiwei, Wang, Guangchuan, Zhu, Zheng-jiang, Song, Bao-Liang, and Xu, Chenqi
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CYTOTOXIC T cells , *T cells , *T-cell exhaustion , *CHOLESTEROL , *CHOLESTEROL metabolism , *MYELOID cells - 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. [Display omitted] • Intratumoral T cells have cholesterol deficiency • CD8+ T cells are more vulnerable to cholesterol deficiency than CD4+ T cells • Cholesterol deficiency induces autophagy-mediated apoptosis of T cells • Oxysterols in the TME cause cholesterol deficiency of T cells by SREBP2/LXR alterations Yan et al. assess the cholesterol atlas of the tumor microenvironment and find that intratumoral T cells have cholesterol deficiency. Mechanistically, oxysterols alter SREBP2/LXR activities to cause cholesterol deficiency in T cells, thus affecting major metabolic and signaling pathways to reduce cell proliferation and to trigger autophagy-mediated apoptosis. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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