Pharmacologic inhibition of liver X receptors enhances T cell anti-tumor function in triple negative breast cancer

Abstract While immunotherapies have demonstrated success in solid malignancies, they have limited efficacy in triple negative breast cancer (TNBC). The liver-X-receptors (LXR) are modulators of metabolism and are known to inhibit pro-inflammatory (Th17 and Th1) and increase anti-inflammatory (Tregs) T-cell differentiation. Colorectal and hematologic cancer cells have also been demonstrated to suppress immune function through production of endogenous LXR agonists. Here we show that targeted suppression of LXR activity using the inverse agonist, SR9243, induces immune-mediated tumor destruction in an orthotopic TNBC model. FACs analysis on tumors revealed a significant increase in Th1 and cytotoxic CD8+ T-cells and a decrease in tumor promoting myeloid derived suppressor cells (MDSCs) in response to SR9243. Intratumor immune cell activation coincided with enhanced dendritic cell (DC) lymph node homing and activity. SR9243 also enhanced Th1 CD4+ and CD8+ cell proliferation in the presence of immune-suppressive tumor conditioned media and cancer cell lysates an in vitro model of the tumor-microenvironment. Metabolic analysis of immune cells exposed to LXR-ligands revealed that LXR activation by tumor-produced ligands or synthetic agonists blocks T-cell glycolytic activity essential to immune cell proliferation and activation in response to tumor antigens. Similarly, we observed that LXR activation disrupts de novo cholesterol synthesis which has been shown to be vital to immune synapse formation between T-cells and DCs. Our results suggest that LXR inverse agonists can be used as immunotherapy drugs to treat TNBC by blocking tumor-induced dysregulation of T-cell metabolism.