LXR-inverse agonism stimulates immune-mediated tumor destruction by enhancing CD8 T-cell activity in triple negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive subtype that is untreatable with hormonal or HER2-targeted therapies and is also typically unresponsive to checkpoint-blockade immunotherapy. Within the tumor microenvironment dysregulated immune cell metabolism has emerged as a key mechanism of tumor immune-evasion. We have discovered that the Liver-X-Receptors (LXRα and LXRβ), nuclear receptors known to regulate lipid metabolism and tumor-immune interaction, are highly activated in TNBC tumor associated myeloid cells. We therefore theorized that inhibiting LXR would induce immune-mediated TNBC-tumor clearance. Here we show that pharmacological inhibition of LXR activity induces tumor destruction primarily through stimulation of CD8+ T-cell cytotoxic activity and mitochondrial metabolism. Our results imply that LXR inverse agonists may be a promising new class of TNBC immunotherapies.

Novel Liver X Receptor Ligand GAC0001E5 Disrupts Glutamine Metabolism and Induces Oxidative Stress in Pancreatic Cancer Cells

“…Compound 1E5 functions as an LXR inverse agonist and as a degrader that decreases LXR protein levels over time. Interestingly, the LXR inverse agonist SR9243 has been shown to inhibit cancer growth by downregulating aerobic glycolysis and fatty acid synthesis and to also affect tumor immunity [ 9 , 10 ]. Targeting cancer metabolism is a promising therapeutic strategy, and metabolic reprogramming driven by oncogenes enables PDACs to survive in hypoxic and nutrient-deprived microenvironments [ 11 ].…”

Antiproliferative and Carbonic Anhydrase II Inhibitory Potential of Chemical Constituents from Lycium shawii and Aloe vera: Evidence from In Silico Target Fishing and In Vitro Testing

“…Table S2: Molecular docking scores and binding interactions of compounds 1-3, 5, 7, and 12 on the selected drug targets. Figure S1: 1 H, 13 C-NMR and ESI-MS spectra of the known compounds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

The versatility of liver X receptors in T cell homeostasis: Location, location, location!

“…However, recent studies also substantiated its ligand-induced anti-proliferative and tumor-suppressive activity, as well as its capability to reduce myeloid-derived suppressor cells within the tumor microenvironment (Dhiman et al, 2018;Tavazoie et al, 2018). On the other hand, an inverse LXR agonist was shown to reduce tumor-associated myeloid-derived suppressor cells, as well as to enhance cytotoxic CD8 T cell-mediated anti-tumor responses in breast cancer through pharmacological LXR inactivation (Carpenter et al, 2019). Both studies show beneficial effects in cancer therapy based on opposite LXR mechanisms, indicating that LXR manipulation by ligand-dependent activation or inactivation depends on the varying preconditions or composition of different tumor microenvironments.…”