Cholesterol-Mediated T-Cell Exhaustion Promotes OSCC Development And Progression

To elucidate the mechanisms by which cholesterol promotes the development and progression of oral squamous cell carcinoma (OSCC). Clinical OSCC samples were collected to detect the levels of low density lipoprotein cholesterol (LDLC) and total cholesterol (TC), and the expression of low density lipoprotein receptor (LDLR) and programmed cell death 1 (PD1). T-cell function and tumor phenotype were further assessed following LDLC treatment in vitro. Moreover, SCC7 tumor-bearing mice model was established to validate the effect of the intervention on dysregulated cholesterol metabolism. The levels of LDLC and TC, and the expression of LDLR and PD1 were significantly higher in tumor tissues compared to para-tumor tissues of OSCC patients. Besides, the colocalization cells of LDLR with PD1 were significantly elevated in high-LDLC tumor tissues than those in low-LDLC tumor tissues. Mechanistically, LDLC caused T cell exhaustion characterized by up-regulation PD1 and CTLA4 and down-regulation of TNFα and IFNγ via the IRE1α-XBP1 endoplasmic reticulum (ER) stress axis, thereby promoting OSCC progression in vitro. Moreover, LDLC promoted tumor growth and impaired the antitumor activity of T cells in vivo. Fluvastatin in combination with PD1 inhibitor reduced tumor cholesterol levels, exhibited potent antitumor effects and reversed the immunosuppressive tumor microenvironment in mice. The dysregulated cholesterol metabolism contributes to the ER stress of T-cells and further mediates immunosuppressive microenvironment, facilitating the continuous progression of OSCC. Targeting cholesterol metabolism and combining with immunotherapy may provide a novel prevention and therapeutic strategy for OSCC.