RORγ bridges cancer-driven lipid dysmetabolism and myeloid immunosuppression
Menée à l'aide de lignées cellulaires, de modèles murins et d'échantillons sanguins prélevés sur des patients atteints d'un cancer du poumon non à petites cellules, d'un cancer colorectal, d'un cancer du sein, d'un adénocarcinoma canalaire du pancréas, d'une tumeur pancréatique neuroendocrine ou d'un cancer des voies biliaires, cette étude met en évidence un mécanisme par lequel la maladie et un régime favorisant l'hypercholestérolémie induisent l'immunosuppression des cellules myéloïdes en activant de manière coopérative ou indépendante le récepteur ROR gamma
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/RORγ), whose transcriptional activity modulates cancer-related emergency myelopoiesis and is boosted by cholesterol metabolites, while hypercholesterolemia itself is associated with dysregulated myelopoiesis. Here, we show that cancer and hypercholesterolemic diet independently or cooperatively activate RORγ-dependent expansion of myeloid-derived suppressor cells (MDSCs) and M2-polarized tumor-associated macrophages (TAMs), supporting cancer spread. Moreover, we report that tumor-induced expression of IL-1b and IL-6 promotes hepatic expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) in preclinical models and patients. Importantly, lowering cholesterol levels, by genetic or pharmacological inhibition of PCSK9, prevents MDSC expansion, M2 TAM accumulation and tumor progression in a RORγ-dependent manner, unleashing specific anti-tumor immunity. Overall, we identify RORγ as a key sensor of lipid disorders, bridging hypercholesterolemia and pro-tumor myelopoiesis.
Cancer Discovery 2024