The cholesterol pathway: impact on immunity and cancer

Frequent alterations in cholesterol homeostasis have classically been thought to support the production of building blocks for growth. However, the immunomodulatory properties of cholesterol, oxysterols, statins, and related metabolites can significantly impact on the mammalian immune system. Targeting cholesterol imbalances might be exploited to hinder tumor growth and restore immune functions in particular malignancies. Excessive cholesterol can lead to CD8+ T cell exhaustion in some models. Recent evidence suggests that targeting the cholesterol pathway could be a therapeutic approach that might synergize with PD-1 checkpoint blockade immunotherapy in some cancers. Immune cells require cholesterol for activation. Therefore, excessive targeting or depletion of cholesterol and subsequent putative effects on immune cells should be major considerations. Targeting the cholesterol pathway might be a promising approach in anticancer therapies. However, careful consideration must be given to the tumor microenvironment and the locations and contexts in which the pathway can be targeted. Cholesterol is a multifaceted metabolite that is known to modulate processes in cancer, atherosclerosis, and autoimmunity. A common denominator between these diseases appears to be the immune system, in which many cholesterol-associated metabolites impact both adaptive and innate immunity. Many cancers display altered cholesterol metabolism, and recent studies demonstrate that manipulating systemic cholesterol metabolism may be useful in improving immunotherapy responses. However, cholesterol can have both proinflammatory and anti-inflammatory roles in mammals, acting via multiple immune cell types, and depending on context. Gaining mechanistic insights into various cholesterol-related metabolites can improve our understanding of their functions and extensive effects on the immune system, and ideally will inform the design of future therapeutic strategies against cancer and/or other pathologies. Cholesterol is a multifaceted metabolite that is known to modulate processes in cancer, atherosclerosis, and autoimmunity. A common denominator between these diseases appears to be the immune system, in which many cholesterol-associated metabolites impact both adaptive and innate immunity. Many cancers display altered cholesterol metabolism, and recent studies demonstrate that manipulating systemic cholesterol metabolism may be useful in improving immunotherapy responses. However, cholesterol can have both proinflammatory and anti-inflammatory roles in mammals, acting via multiple immune cell types, and depending on context. Gaining mechanistic insights into various cholesterol-related metabolites can improve our understanding of their functions and extensive effects on the immune system, and ideally will inform the design of future therapeutic strategies against cancer and/or other pathologies. one of the parallel metabolic pathways of cholesterol synthesis downstream of lanosterol; lanosterol produces cholesterol via sequential conversions into desmosterol, which requires final desaturation by 24-dehydrocholesterol reductase to produce cholesterol. a rare, autosomal recessive genetic disorder caused by mutations in the mevalonate kinase (MVK) gene; the disorder is characterized by recurrent febrile episodes typically associated with lymphadenopathy, abdominal pain, and elevated serum polyclonal immunoglobulin D (IgD) titers. immunotherapy drugs that block immune checkpoint proteins from binding to their partner proteins. Immune checkpoints include key pathways in the immune system that signal via molecules/receptors (e.g., PD-1, PD-L1, and CTLA-4) to modify cell functions. In the case of the examples listed, these inhibitory receptors counter activation, and at steady-state some of their functions include limiting immune cell toxicity (e.g., to avoid fratricide) and overactivation, and contribute to establishing tolerance. a multiprotein complex that acts as an innate immunity sensor and contributes to regulating inflammatory pathways; it activates caspase-1 to induce inflammation and cell death through pyroptosis. one of the parallel metabolic pathways of cholesterol synthesis; downstream conversions of lanosterol cause desaturation carried out by 24-dehydrocholesterol reductase to produce cholesterol. a receptor belonging to the nuclear receptor family of transcription factors; controls the production of cholesterol, among others. Oxysterols activate LXR to decrease intracellular cholesterol. an inborn error of metabolism caused by MVK mutations that is characterized by dysmorphology, psychomotor retardation, progressive cerebellar ataxia, and recurrent febrile crises. proinflammatory macrophages known for their immune response and lytic capabilities. anti-inflammatory macrophages known for their role in wound healing and tissue repair. immature myeloid cells with strong immunosuppressive properties; can inhibit adaptive and innate immune responses either directly or indirectly. a cytotoxic innate immune cell known for killing without priming, and instead operate via a balance of inhibitory and activating signals. a subset of B cells that exert immunoregulatory functions a transcription factor that can be activated by oxysterols to induce the expression of SREBP2 downstream genes, including those in the cholesterol pathway. monitors cholesterol concentration in the endoplasmic reticulum (ER). If the concentration is low, it acts as a chaperone that enables SREBPs to migrate to the Golgi where they are cleaved and activated, and subsequently migrate to the nucleus to promote the expression of target genes. transcription factors that regulate lipid and fatty acid synthesis (SREBP1) and cholesterol concentrations (SREBP2). unconventional T cells with T cell receptors (TCR) containing γ and δ chains. γδ T cells play a role in recognizing lipid antigens and in responding to danger signals; they play important roles in mucosal tissues. a stepwise and progressive loss of T cell effector functions associated with chronic antigen exposure, for example in cancer and chronic infections.