In a study published in Cell Chemical Biology, teams led by Dr. XU Chenqi from the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, collaborated with Dr. WANG Haopeng from ShanghaiTech University and Dr. LOU Jizhong from the Institute of Biophysics, Chinese Academy of Sciences, discovered that the natural sterol metabolite 7a-hydroxycholesterol (7a-HC) can directly inhibit TCR (T Cell Receptor) signal transduction. Utilizing this function, the researchers demonstrated that short-term treatment with 7a-HC can reduce basal TCR-T cell signaling, increase the proportion of memory cells, and thereby enhance the long-term efficacy of immunotherapy.

Cholesterol molecules can be oxidized at multiple sites, producing various hydroxycholesterols (oxidized cholesterols). Cholesterol can enhance the immune function of CD8 T cells; however, hydroxycholesterols exhibit significant immunosuppressive functions, inhibiting normal T cell immune responses in the tumor microenvironment . Nevertheless, the immune system operates as a balanced system where unfavorable factors can be converted into beneficial ones in appropriate contexts, creating new immunotherapy strategies.

The CD3ε subunit in the TCR/CD3 complex contains a juxtamembrane basic residue-rich sequence (JM-BRS) that can electrostatically interact with negatively charged phospholipids in the plasma membrane. This interaction inserts the JM-BRS and the adjacent tyrosine-based signaling motifs (ITAMs) into the membrane, restricting JM-BRS's recruitment of Lck kinase and Lck's phosphorylation of ITAMs. Due to the presence of hydroxyl groups at positions 3 and 7, 7a-HC can reduce the packing density of lipid molecules in the cell membrane, making the membrane structure looser. This helps the intracellular region of CD3ε insert better into the membrane, thereby inhibiting TCR signal transduction.

TCR signaling is a double-edged sword: it activates and proliferates T cells, granting them effector functions, but also accelerates terminal differentiation, weakening T cell memory. Therefore, TCR signaling needs to be controlled at an appropriate level to achieve sufficient T cell effector functions while maintaining a degree of stemness, ensuring a robust and long-lasting T cell immune response. Leveraging 7a-HC's TCR signaling inhibitory function, the research team conducted several short-term treatments (each lasting 20 minutes) during the in vitro expansion of TCR-T cells. This significantly suppressed basal T cell signaling and markedly increased the proportion of memory T cells. 7a-HC-treated TCR-T cells demonstrated significant advantages in long-term tumor killing, as evidenced by better tumor control in animal models. This study reveals a new regulatory mechanism of TCR signaling and proposes a new strategy for TCR-T cell therapy.

Contact: cqxu@sibcb.ac.cn  

Reference: https://www.sciencedirect.com/science/article/pii/S2451945624001673

In a study published in EMBO Molecular Medicine, Prof. XU Chenqi's team from the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences, Prof. ZHU Zheng-Jiang's team from the Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, and Prof. WANG Zhigang's team from the Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital reported that the asynchronous cholesterol biosynthesis in MSS CRC shapes tumor immune landscape through a Th17-modulation mechanism.

Cancer immunotherapies have experienced significant success in recent years. However, many types of cancers exhibit poor responses to current immunotherapies. Colorectal cancer with microsatellite stability (MSS CRC), constituting the majority subtype of CRC (approximately 85% of patients), demonstrates insensitivity to immune checkpoint blockade therapies. Additionally, MSS CRC is reported to exhibit an enrichment of a pro-inflammatory CD4+ T cell subset known as Th17 in the tumor microenvironment. This subset has been implicated in mediating PD-1 resistance in various cancer types. Therefore, there is a strong interest in investigating the mechanisms behind the Th17 enrichment observed in MSS CRC.

In this study, a metabolic cue responsible for the Th17 enrichment in MSS CRC is reported through the examination of large human cohorts and animal models. The researchers discovered that MSS CRC cells can induce T cell polarization toward the Th17 lineage by secreting distal cholesterol precursors (DCPs). The cholesterol biosynthesis pathway is asynchronously upregulated in MSS CRC cells, resulting in the abnormal accumulation of DCPs. By inhibiting Cyp51, the cholesterol biosynthesis upstream enzyme, and thereby reducing intratumoral DCPs, tumor progression of MSS CRC was suppressed through a Th17-modulation mechanism.

This study reveals a novel mechanism of cancer-immune interaction and an intervention strategy for the difficult-to-treat MSS CRC.

Contact: cqxu@sibcb.ac.cn

Reference: https://www.embopress.org/doi/full/10.1038/s44321-023-00015-9

The international academic journal PNAS published online the latest research of Lou Jizhong's research group from the Institute of Biophysics, Xu Chenqi's research group from the Center for Excellence in Molecular Cell Science, and Chen Wei's research group from Zhejiang University School of Medicine, "Self-programmed dynamics of T cell receptor condensation". This work found that the T cell receptor (TCR) regulates T cell activation through a self-programmed aggregation and depolymerization mechanism based on CD3ε/Lck, which explained the sensitivity and rapidity of the TCR signaling pathway from the perspective of phase separation and further enriched the Csk-based negative regulation mechanism of TCR.

Dr. Chen Hui from the Institute of Biophysics, Xu Xinyi, a doctoral student at the Center for Excellence in Molecular and Cell Science, and Dr. Hu Wei, a distinguished researcher at the Nephrology Center of the First Affiliated Hospital of Zhejiang University School of Medicine, are the co-first authors of this article. Professor Lou Jizhong, Xu Chenqi, and Chen Wei are the co-corresponding authors. Director Lou Changjie of Harbin Medical University Cancer Hospital, Professor Liu Wanli of Tsinghua University, and Professor Jiang Ning of the University of Pennsylvania also made important contributions to this study. The research work was funded by the Natural Science Foundation of China, the Strategic Pioneering Technology Project of the Chinese Academy of Sciences (Category B), and the National Key Research and Development Project.

Recently, Cancer Cell published the research from Dr. Chenqi Xu’s group at Hangzhou Institute for Advanced Study and CAS Center for Excellence in Molecular Cell Science and Dr. Bao-Liang Song’s group at Wuhan University entitled “Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity”. This study revealed a new mechanism of TME inducing T-cell dysfunction through cholesterol metabolism. Oxysterols in TME cause cholesterol deficiency of intratumoral T cells, subsequently leading to aberrant metabolic and signaling pathways that drive T cell exhaustion/dysfunction.

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 of intratumoral cells. The authors firstly characterized the cholesterol atlas of the TME and found that TILs had cholesterol deficiency while immunosuppressive myeloid cells and tumor cells had cholesterol abundance and consume most of the environmental cholesterol. Then the authors found that low cholesterol levels inhibited T-cell proliferation and caused autophagy-mediated apoptosis, particularly for cytotoxic T cells. The authors further revealed that oxysterols enriched in the TME mediated reciprocal alterations of 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. The authors developed a new cholesterol-modulation strategy to improve the performance of CAR-T cells. LXRb depletion in CAR-T cells led to improved antitumor function against solid tumor. 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.

Postdoc Chengsong Yan from Hangzhou Institute for Advanced Study and CAS Center for Excellence in Molecular Cell Science, Ph.D. candidates Lin Zheng, Shutan Jiang, Haochen Yang and Postdoc Jun Guo from CAS Center for Excellence in Molecular Cell Science are the co-first authors. Dr. Chenqi Xu and Dr. Bao-Liang Song are the co-corresponding authors.