Abstract 1901: Diglyceride acyltransferase 1 reprograms lipid metabolism in myeloid-derived suppressor cells and augments immune checkpoints cancer immunotherapy

Abstract

Abstract A better understanding of the tumor immune microenvironment and current challenges facing immunotherapy will advance research in pursuit of effective cancer therapy. Although huge clinical successes have been recorded with the blockade of programmed death-1 receptor/programmed death-ligand 1 (PD-1/PD-L1) signaling pathway, studies have shown that immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) contribute to its resistance in a fraction of cancer patients. Our group and others previously showed that lipid metabolism drives the immunosuppressive attribute of MDSCs thus leading to the inability of T-cells activation for anti-tumor activity. Lipidomics analysis showed that triglyceride species are increased in tumor-bearing mice compared to their control counterparts; however, it remains unreported if triglyceride synthesis could contribute to MDSCs suppressive function in cancer. Here we found an increased expression of diglyceride acyltransferase 1(DGAT1) in MDSCs, a key enzyme regulating exogenous fatty acid uptake for triglyceride synthesis. MDSCs generated in the presence of unsaturated fatty acids upregulated DGAT1 expression. Therapeutic targeting of DGAT1 in MDSCs cultured in the presence of tumor explanted supernatant (TES) and unsaturated fatty acids reduced lipid accumulation and their suppressive function on T-cells. Also, inhibiting DGAT1 expression in TES-induced MDSCs downregulated mRNA for ARG1, IL-6, and IL-10. Treatment with DGAT1 inhibitor compromised tumor growth in melanoma-B16F10 and Lewis lung carcinoma-LLC bearing C57/BL6 mice. Immune cell profile data showed a decreased population of MDSCs, polymorphonuclear-MDSCs, and macrophages, but an increased proportion of CD3, CD4, CD8, and dendritic cells while there was no significant change in monocytic-MDSCs from the tumor of mice treated with DGAT1 inhibitor. On the contrary, DGAT1 blockade in immunocompromised mice failed to reduce B16F10-tumor progression, this suggests that the effect of the DGAT1 inhibitor may be immune dependent. Remarkably, DGAT1 inhibition provided additional therapeutic benefits for immune checkpoint blockade (ICB) and delayed B16F10 and LLC growth in immunocompetent mice. Combination treatment of DGAT1 and anti-PD-L1 antibody blocked MDSCs accumulation and their immunosuppressive function leading to reactivation of T cells anti-tumor response through enhanced production of TNFα and IFN-γ. Altogether, our data demonstrate that DGAT1 promotes the immunosuppressive role of MDSCs and suggest a new target to inhibit MDSCs function; hence, improve the efficacy of ICB in cancer therapy. Citation Format: Adeleye Oluwatosin Adeshakin, Dehong Yan, Funmilayo O. Adeshakin, Lukman O. Afolabi, Menqgi Zhang, Xiaochun Wan. Diglyceride acyltransferase 1 reprograms lipid metabolism in myeloid-derived suppressor cells and augments immune checkpoints cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1901.