SCD1 抑制通过 ACAT1 依赖性降低酯化胆固醇增强 CD8⁺ T 细胞的效应功能

We previously reported that the inhibition of stearoyl-CoA desaturase 1 (SCD1) enhances the antitumor function of CD8 + T cells indirectly via restoring production of DC recruiting chemokines by cancer cells and subsequent induction of antitumor CD8 + T cells. In this study, we investigated the molecular mechanism of direct enhancing effects of SCD1 inhibitors on CD8 + T cells. In vitro treatment of CD8 + T cells with SCD1 inhibitors enhanced IFN- production and cytotoxic activity of T cells along with decreased oleic acid and esterified cholesterol, which is generated by cholesterol esterase, acetyl-CoA acetyltransferase 1 (ACAT1), in CD8 + T cells.

The addition of oleic acid or cholesteryl oleate reversed the enhanced functions of CD8 + T cells treated with SCD1 inhibitors. Systemic administration of SCD1 inhibitor to MCA205 tumor-bearing mice enhanced IFN- production of tumor-infiltrating CD8 + T cells, in which oleic acid and esterified cholesterol, but not cholesterol, were decreased.

These results indicated that SCD1 suppressed effector functions of CD8 + T cells through the increased esterified cholesterol in an ACAT1-dependent manner, and SCD1 inhibition enhanced T cell activity directly through decreased esterified cholesterol.

Finally, SCD1 inhibitors or ACAT1 inhibitors synergistically enhanced the antitumor effects of anti-PD-1 antibody therapy or CAR-T cell therapy in mouse tumor models.

Therefore, the SCD1-ACAT1 axis is regulating effector functions of CD8 + T cells, and SCD1 inhibitors, and ACAT1 inhibitors are attractive drugs for cancer immunotherapy.