RORγ Bridges Cancer-Driven Lipid Dysmetabolism and Myeloid Immunosuppression

Despite well-documented metabolic and hematopoietic alterations during tumor development, the mechanisms underlying this crucial immunometabolic intersection remain elusive. Of particular interest is the connection between lipid metabolism and the retinoic acid-related orphan receptor (RORC1/ROR gamma), whose transcriptional activity modulates cancer-related emergency myelopoiesis and is boosted by cholesterol metabolites, whereas hypercholesterolemia itself is associated with dysregulated myelopoiesis. In this study, we show that cancer and hypercholesterolemic diet independently or cooperatively activate ROR gamma-dependent expansion of myeloid-derived suppressor cells (MDSC) and M2-polarized tumor-associated macrophages (TAM), supporting cancer spread. Moreover, we report that tumor-induced expression of IL1 beta and IL6 promotes hepatic expression of proprotein convertase subtilisin/kexin type 9 in preclinical models and patients. Importantly, lowering cholesterol levels, by genetic or pharmacologic inhibition of proprotein convertase subtilisin/kexin type 9, prevents MDSC expansion, M2 TAM accumulation, and tumor progression in a ROR gamma-dependent manner, unleashing specific antitumor immunity. Overall, we identify ROR gamma as a key sensor of lipid disorders, bridging hypercholesterolemia and protumor myelopoiesis.Significance: Cancer and a hypercholesterolemic diet independently or collaboratively increase blood cholesterol, which in turn triggers ROR gamma-dependent expansion of suppressive monocytic MDSCs and M2-like TAMs, thus inhibiting specific antitumor immunity and facilitating disease progression.