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Published on: August 15, 2019
RORγ Bridges Cancer-Driven Lipid Dysmetabolism and Myeloid Immunosuppression
Augusto Bleve1,2, Martina Incerti1,2, Francesca Maria Consonni1,2
1Department of Pharmaceutical Sciences, University of Piemonte Orientale "A. Avogadro", Novara, Italy.
Abstract:
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, whereas hypercholesterolemia itself is associated with dysregulated myelopoiesis. In this study, we show that cancer and hypercholesterolemic diet independently or cooperatively activate RORγ-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 IL1β 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 RORγ-dependent manner, unleashing specific antitumor immunity. Overall, we identify RORγ 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 RORγ-dependent expansion of suppressive monocytic MDSCs and M2-like TAMs, thus inhibiting specific antitumor immunity and facilitating disease progression.
Insights
This study reveals that high cholesterol and cancer activate RORγ, promoting immune suppression and tumor growth. Lowering cholesterol by inhibiting PCSK9 blocks this pathway, enhancing anti-tumor immunity.
Area of Science:
- Immunometabolism
- Oncology
- Lipid Metabolism
Background:
- Tumor development involves metabolic and hematopoietic changes, but the immunometabolic intersection is poorly understood.
- The retinoic-acid-related orphan receptor gamma (RORγ) links lipid metabolism to cancer-related myelopoiesis.
- Hypercholesterolemia is associated with dysregulated myelopoiesis, suggesting a role for lipid disorders in cancer progression.
Purpose of the Study:
- To investigate the role of RORγ in mediating the effects of hypercholesterolemia and cancer on immune cells.
- To elucidate the mechanisms by which lipid metabolism influences tumor-associated immune suppression.
- To identify therapeutic strategies targeting the RORγ-lipid metabolism axis in cancer.
Main Methods:
- Utilized preclinical cancer models and patient data.
- Investigated the impact of cancer and hypercholesterolemic diets on RORγ activity and immune cell populations (MDSCs, TAMs).
- Examined the role of IL-1β, IL-6, and PCSK9 in regulating hepatic gene expression and cholesterol levels.
- Assessed the effects of PCSK9 inhibition on tumor progression and anti-tumor immunity.
Main Results:
- Cancer and hypercholesterolemic diets independently or together activate RORγ, leading to myeloid-derived suppressor cell (MDSC) expansion and M2-polarized tumor-associated macrophage (TAM) accumulation.
- Tumor-induced IL-1β and IL-6 promote hepatic PCSK9 expression.
- Inhibition of PCSK9, which lowers cholesterol, prevents MDSC expansion and M2 TAM accumulation in a RORγ-dependent manner.
- Lowering cholesterol levels unleashes specific anti-tumor immunity and inhibits tumor progression.
Conclusions:
- RORγ acts as a critical sensor linking lipid disorders, specifically hypercholesterolemia, to pro-tumor myelopoiesis.
- The RORγ-PCSK9 axis represents a key pathway in cancer immune evasion driven by metabolic alterations.
- Targeting PCSK9 to reduce cholesterol levels offers a potential therapeutic strategy to enhance anti-tumor immunity and combat cancer progression.
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