RORα Regulates Cholesterol Metabolism of CD8+ T Cells for Anticancer Immunity

Lee, In Kyu; Song, Hyerin; Kim, Hyerim; Kim, Ik Soo; Tran, Na Ly; Kim, Sang‐Heon; Oh, Se H.; Lee, Ji Min

doi:10.3390/cancers12071733

Cited by 35 publications

(21 citation statements)

References 58 publications

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“…Conssistent with a previous report, when co-infused TRP-1 Th17 and pmel-1 Tc17 cells generated in vitro in the presence of the RORγ agonist, mice with melanoma tumors were protected for more than two months after tumor challenges of over three times, indicating that RORγ agonist-primed cells possessed a stem-like memory phenotype and provided a long-term protection against tumor challenges [ 117 ]. Furthermore, the RORα synthetic agonist SR1078 was reported to remarkably increase CD8+ T cell effector responses to anticancer immunity role [ 118 ]. Doxorubicin, which is developed from a metabolite of the bacterium Streptomyces peucetius var.…”

Section: Clock Drugs For the Immunotherapy Of Cancermentioning

confidence: 99%

Circadian clock: a regulator of the immunity in cancer

et al. 2021

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The circadian clock is an endogenous timekeeper system that controls and optimizes biological processes, which are consistent with a master circadian clock and peripheral clocks and are controlled by various genes. Notably, the disruption of circadian clock genes has been identified to affect a wide range of ailments, including cancers. The cancer-immunity cycle is composed of seven major steps, namely cancer cell antigen release and presentation, priming and activation of effector immunity cells, trafficking, and infiltration of immunity to tumors, and elimination of cancer cells. Existing evidence indicates that the circadian clock functions as a gate that govern many aspects of the cancer-immunity cycle. In this review, we highlight the importance of the circadian clock during tumorigenesis, and discuss the potential role of the circadian clock in the cancer-immunity cycle. A comprehensive understanding of the regulatory function of the circadian clock in the cancer-immunity cycle holds promise in developing new strategies for the treatment of cancer.

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Section: Clock Drugs For the Immunotherapy Of Cancermentioning

confidence: 99%

Circadian clock: a regulator of the immunity in cancer

et al. 2021

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“…ATRA regulates differentiation of naive T cells to Treg cells through induction of FoxP3 transcription factor [229] , [246] , [247] and TGF-β potentiates this effect of ATRA [244] . Hence, RA blocks the differentiation of Th17 cells and induces Tregs in the presence of TGF-β by reciprocally down-regulating RORγt and activating FoxP3 expression in T cells [233] , [248] , [249] . Like a regulatory switch, ATRA largely inhibits Th17-mediated inflammation and autoimmunity [234] , [241] .…”

Section: Immune System Involvement and Retinoid Signaling Disorder In Covid-19mentioning

confidence: 99%

A novel hypothesis for COVID-19 pathogenesis: Retinol depletion and retinoid signaling disorder

Sarohan¹,

Kızıl

İnkaya

et al. 2021

Cellular Signalling

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The SARS-CoV-2 virus has caused a worldwide COVID-19 pandemic. In less than a year and a half, more than 200 million people have been infected and more than four million have died. Despite some improvement in the treatment strategies, no definitive treatment protocol has been developed. The pathogenesis of the disease has not been clearly elucidated yet. A clear understanding of its pathogenesis will help develop effective vaccines and drugs. The immunopathogenesis of COVID-19 is characteristic with acute respiratory distress syndrome and multiorgan involvement with impaired Type I interferon response and hyperinflammation. The destructive systemic effects of COVID-19 cannot be explained simply by the viral tropism through the ACE2 and TMPRSS2 receptors. In addition, the recently identified mutations cannot fully explain the defect in all cases of Type I interferon synthesis. We hypothesize that retinol depletion and resulting impaired retinoid signaling play a central role in the COVID-19 pathogenesis that is characteristic for dysregulated immune system, defect in Type I interferon synthesis, severe inflammatory process, and destructive systemic multiorgan involvement. Viral RNA recognition mechanism through RIG-I receptors can quickly consume a large amount of the body's retinoid reserve, which causes the retinol levels to fall below the normal serum levels. This causes retinoid insufficiency and impaired retinoid signaling, which leads to interruption in Type I interferon synthesis and an excessive inflammation. Therefore, reconstitution of the retinoid signaling may prove to be a valid strategy for management of COVID-19 as well for some other chronic, degenerative, inflammatory, and autoimmune diseases.

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“…For example, RORα responds to metabolic changes and influences cholesterol synthesis pathways in cytotoxic T cells by inhibiting NF-κB target genes. The contributions of these activities to cytotoxic CD8+ T cells have been verified using RORα agonists 49 . Pharmacological stimulation of RORα using cholesterol sulfate and the synthetic agonist SR1078 activates downstream target genes of RORα, whereas the synthetic specific antagonist SR3335 functions as a selective inhibitor of RORα.…”

Section: Anti-inflammatory Mechanisms Involving Rorαmentioning

confidence: 97%

Unraveling the physiological roles of retinoic acid receptor-related orphan receptor α

2021

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Retinoic acid receptor-related orphan receptor-α (RORα) is a member of the orphan nuclear receptor family and functions as a transcriptional activator in response to circadian changes. Circadian rhythms are complex cellular mechanisms regulating diverse metabolic, inflammatory, and tumorigenic gene expression pathways that govern cyclic cellular physiology. Disruption of circadian regulators, including RORα, plays a critical role in tumorigenesis and facilitates the development of inflammatory hallmarks. Although RORα contributes to overall fitness among anticancer, anti-inflammatory, lipid homeostasis, and circadian clock mechanisms, the molecular mechanisms underlying the mode of transcriptional regulation by RORα remain unclear. Nonetheless, RORα has important implications for pharmacological prevention of cancer, inflammation, and metabolic diseases, and understanding context-dependent RORα regulation will provide an innovative approach for unraveling the functional link between cancer metabolism and rhythm changes.

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RORα Regulates Cholesterol Metabolism of CD8+ T Cells for Anticancer Immunity

Cited by 35 publications

References 58 publications

Circadian clock: a regulator of the immunity in cancer

Circadian clock: a regulator of the immunity in cancer

A novel hypothesis for COVID-19 pathogenesis: Retinol depletion and retinoid signaling disorder

Unraveling the physiological roles of retinoic acid receptor-related orphan receptor α

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