Blockade of diacylglycerol transferase 1 reprograms lipid accumulation in myeloid-derived suppressor cells and suppressed tumor progression

Abstract

Abstract Immunotherapy, a way of restoring immune response and anti-cancer immunity, has revolutionized cancer therapy. However, immunosuppressive cells such as myeloid-derived suppressor cells (MDSC) still represent a significant impediment to immunotherapy, contributing to therapy failure and poor clinical responses. We previously reported that uptake of polyunsaturated fatty acid (PUFA) by MDSCs led to lipid accumulation via upregulation of fatty acid transport protein 2 (FATP2) to induce ROS-mediated immunosuppressive function thereby impairing T-cells activation to demonstrate their anti-tumor effect. Here lipidomics analysis revealed the exact lipid species accumulated in MDSCs from tumor-bearing tissues to be phospholipids and triglycerides (TAG). Interestingly, we observed significantly increased expression of a key enzyme involved in TAG synthesis - diacylglycerol transferase 1 (DGAT1), in MDSCs of Lewis lung carcinoma (LLC) and melanoma (B16F10)-bearing mice. Inhibiting DGAT1 reduced neutral lipid accumulation in MDSCs. Also, DGAT1 blockade downregulated MDSCs immunosuppressive genes and decreased MDSCs immunosuppressive function. Remarkably, blockade of DGAT1 expression reduced MDSCs and macrophages, thus abrogated tumor growth. Altogether, our study identified an unreported lipid metabolic target in MDSCs that promises a novel therapeutic option in clinical settings to enhance cancer immunotherapy. This work was supported by the National Key R&D Program of China (2019YFA0906100), National Natural Science Foundation of China (Grants 82071772, 81501356 and 81373112), Key-Area R&D Program of Guangdong Province (2019B020201014).