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
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