The study reveals the mechanism and functional importance of cholesterol deficiency in T cells within tumors

On May 23, the international academic journal Cancer Cell published online the latest research results “Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of” jointly completed by the Xu Chenqi research group of the Hangzhou Advanced Research Institute of the National University of Science and Technology/the Excellence Innovation Center for Molecular Cell Science of the Chinese Academy of Sciences and the research group of Song Baoliang of the School of Life Sciences of Wuhan University antitumor immunity”。 The work discovered a novel mechanism by which the tumor microenvironment triggers T lymphocyte incapacitation through cholesterol metabolism. Oxidized cholesterol enriched in the tumor microenvironment can cause cholesterol deficiency in tumor-infiltrating T lymphocytes, resulting in abnormal metabolism and signaling pathways and disabling T cells.

Various immune cells in the tumor microenvironment can significantly influence tumor initiation and progression. Tumor-infiltrating lymphocytes (TILs) recognize and kill tumor cells, while myeloid cells, mainly tumor-associated macrophages (TAMs) and neutrophils, perform tumor-promoting and immunosuppressive functions. T lymphocytes are depleted and disabled after entering the tumor microenvironment, reducing their ability to clear the tumor. There are many causes of T cell depletion and incapacitation, one of which is chronic antigen stimulation and the other is metabolic changes caused by the tumor microenvironment. Cholesterol is the main component of cell membrane structure and is needed by all mammalian cells. Xu Chenqi’s team found in previous studies that by regulating the cholesterol metabolism of T cells, their anti-tumor ability can be enhanced (Nature 2016). However, the cholesterol metabolism status of various immune cells in the tumor microenvironment and the degree of dependence on cholesterol metabolism are not well understood. Whether tumor-infiltrating lymphocytes have too high or too low cholesterol levels and that dysregulated cholesterol metabolism affect the function of tumor-infiltrating lymphocytes is unclear. In addition, whether clinically tested drugs targeting cholesterol metabolism are beneficial or harmful to immune cells needs to be carefully evaluated. Addressing these fundamental questions could provide important information for understanding cancer and immunity and could lead to new strategies for metabolic intervention.

Through the analysis of cholesterol maps of tumor-infiltrating cells, it was found that lymphocytes in the tumor microenvironment were deficient in cholesterol, while immunosuppressive myeloid cells and tumor cells were rich in cholesterol. Further studies have found that low cholesterol levels inhibit T cell proliferation and trigger autophagy-mediated apoptosis, especially for cytotoxic T cells. Sterolomics methods were used to enrich oxidized cholesterol in the tumor microenvironment, and oxidized cholesterol inhibited the SREPB2 pathway to activate the LXR pathway, thereby causing T cell cholesterol deficiency. This further leads to abnormal metabolism and signaling pathways that lead to T cell incapacitation. The study also tested cholesterol normalization strategies in CAR-T treatment for solid tumors and found that LXRb knockout improved the anti-solid tumor ability of CAR T cells. This study systematically studied the cholesterol metabolism status of T lymphocytes in the tumor microenvironment, which provided a theoretical basis for further treatment of tumors by targeting cholesterol metabolism.

Yan Chengsong, postdoctoral fellow at Hangzhou Institute for Advanced Study of UCAS, Zheng Lin, doctoral student Zheng Shutan, doctoral student Jiang Shutan, doctoral student Yang Haochen, and postdoctoral fellow Guo Jun of the Center of Excellence of Molecular Cells are the co-first authors of the paper. Professor Chenqi Xu from the School of Life and Health, Hangzhou Advanced Research Institute of UCASTs/Center for Excellence in Molecular Cell Sciences, Chinese Academy of Sciences, and Professor Baoliang Song from the School of Life Sciences, Wuhan University, are the corresponding authors of this paper. The research was also supported by researcher Zhu Zhengjiang from the Intersection Center of Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences. The project is funded by the Chinese Academy of Sciences, the National Natural Science Foundation of China, the Ministry of Science and Technology, and the Ministry of Education. The research work is supported by the Cell Biology Technology Platform, the Molecular Biology Technology Platform and the Animal Experiment Technology Platform of the Center of Excellence for Molecular Cells. (Source: Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences)

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