Regulation of cutaneous immune function and anti-tumor immune responses by PPARgamma-mediated transrepressive signaling

PPARgamma 介导的反式抑制信号调节皮肤免疫功能和抗肿瘤免疫反应

• 批准号: 9898276
• 负责人: RAYMOND L KONGER
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898276
• 关键词: Abscopal effect; Agonist; Antitumor Response; Area; Biological; C57BL/6 Mouse; Chemopreventive Agent; Classification Scheme; Cleaved cell; Complex; Confusion; Contact hypersensitivity; Cutaneous; Data; Defect; Effectiveness; Epidermis; Event; Exhibits; Exposure to; External Beam Radiation Therapy; Genes; Growth; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunocompetent; Immunosuppression; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Integral Membrane Protein; Intervention; Ionizing radiation; Length; Ligands; Malignant Neoplasms; Mediating; Methods; Military Personnel; Mus; Nuclear Protein; Nuclear Receptors; Oxidative Stress; PPAR gamma; Peroxisome Proliferators; Pharmaceutical Preparations; Play; Population; Process; Production; Proteins; Radiation therapy; Regulation; Response Elements; Roentgen Rays; Role; Signal Pathway; Signal Transduction; Skin Cancer; Skin Neoplasms; Sun Exposure; Sunlight; System; T-Lymphocyte; TNF gene; Testing; Time; Transactivation; Transforming Growth Factors; Transplantation; Tumor Antigens; Tumor Necrosis Factor Activation; UV Radiation Exposure; UV induced; UVB induced; Ultraviolet Rays; Veterans; Wild Type Mouse; X-Ray Therapy; anti-PD-1; anti-PD-L1; anti-tumor immune response; anticancer activity; antitumor effect; base; cancer risk; cis acting element; design; factor A; genetic corepressor; high risk; immune function; immunogenic; immunoregulation; improved; in vivo; insight; lipid biosynthesis; melanoma; neoplastic cell; pre-clinical; response; rosiglitazone; side effect; tumor; tumor growth; tumorigenesis; ultraviolet

Skin cancer is primarily caused by environmental ultraviolet (UV) exposure from sunlight. We have shown that loss of peroxisome proliferator activated receptor gamma (PPARγ) in the epidermis of mice (Pparg-/-epi mice) promotes UV-induced skin cancer formation. We have also shown that the PPARγ agonist rosiglitazone (Rosig) protects mice against skin cancer formation. The historical method for classifying PPARγ ligands is by their ability to activate genes associated with adipogenesis through a process called transactivation. However, PPARγ ligands that both activate and suppress transactivation have been shown to exhibit anti-tumor activity. This has created confusion regarding the anti-tumor effects of PPARγ. However, some PPARγ ligands also exhibit the ability to suppress the expression of other genes through a distinctly different mechanism called “transrepression”. We hypothesize that PPARγ ligand-dependent transrepression, rather than transactivation, is key to the anti-tumor activity of PPARγ. UV suppresses T-cell mediated contact hypersensitivity (CHS) responses as well as anti-tumor immune responses (termed UV-induced immunosuppression (UV-IS)). UV-IS likely promotes skin cancer formation by promoting tolerance to tumor-specific antigens. We show that loss of epidermal PPARγ produces an immunosuppressive state resulting in a marked defect in CHS responses as well as enhanced skin tumor growth. We also show that Rosig treatment blocks UV-IS and suppresses skin tumor growth in immune competent, but not immunodeficient mouse hosts. We hypothesize that PPARγ activation suppresses UV-induced skin cancer formation at least in part by its ability to transrepress signaling pathways involved in UV-IS. In particular, we show that PPARγ transrepresses a protein called tumor necrosis factor α (TNF-α) that is present as both a full-length transmembrane form and a soluble proteolytically cleaved form. We propose that the transmembrane form (tmTNF-α) is primarily involved in immune suppression. Thus, PPARγ ligands may prove useful as long-term chemopreventive agents that would promote immune-mediated clearance of nascent skin tumors in individuals at high risk for skin cancer. Finally, recent studies have shown that radiation therapy, like UV, also promotes systemic immunosuppression through its ability to induce oxidative stress. We propose that transrepressive PPARγ ligands will reverse this immune suppression and promote the so-called abscopal effect. This abscopal effect results in anti-tumor responses in tumors that are outside the field of radiation treatment. Although spontaneous abscopal effects occur rarely, evidence exists that efforts to promote immune responses can make this response commonplace. We propose that transrepressive PPARγ ligands will act in concert with radiotherapy to promote the abscopal effect. To examine our hypothesis, the studies will be divided into the following three specific aims (SA): SA#1: Determine whether epidermal PPARγ regulates CHS responses through transmembrane TNF-α (tmTNF-α) rather than soluble TNF-α (solTNF-α). SA#2: Determine the capacity of diverse PPARγ ligands to induce PPARγ-specific transrepression of UVB-induced NF-κB activation and TNF-α production in vitro and in vivo. We will correlate this transrepressive activity with the ability to reverse UV-induced suppression of CHS responses. SA#3: Determine whether transrepressive PPARγ ligands promote anti-tumor immune responses either alone or following external beam radiation therapy. These studies will demonstrate the importance of transrepressive PPARγ ligand-dependent signaling in regulating anti-tumor immune responses. It will also provide mechanistic insight into how PPARγ activation acts to suppress tumorigenesis and promote anti-tumor immune responses and provide a rationale for the use of transrepressive PPARγ ligands as chemopreventive agents or as an adjunct to current radiotherapy.

皮肤癌主要是由来自阳光的环境紫外线（UV）暴露引起的。我们已经证明 小鼠（Pparg-/-epi小鼠）表皮中过氧化物酶体增殖物激活受体γ（PPAR γ）的丢失 促进紫外线诱导的皮肤癌形成。我们还发现，PPAR γ激动剂罗格列酮 （Rosig）保护小鼠免受皮肤癌形成。对PPAR γ配体进行分类的历史方法是： 它们通过一种称为反式激活的过程激活与脂肪形成相关的基因的能力。然而，在这方面， 激活和抑制反式激活的PPAR γ配体已显示出抗肿瘤活性。 这造成了关于PPAR γ抗肿瘤作用的混淆。然而，一些PPAR γ配体也 表现出通过一种明显不同的机制抑制其他基因表达的能力， "反阻遏"。我们假设，PPAR γ配体依赖的反式抑制，而不是反式激活， 是PPAR γ抗肿瘤活性的关键。UV抑制T细胞介导的接触性超敏反应（CHS） 抗肿瘤免疫反应（称为UV诱导的免疫抑制（UV-IS））。紫外-IS 可能通过促进对肿瘤特异性抗原的耐受性来促进皮肤癌的形成。我们发现， 表皮PPAR γ产生免疫抑制状态，导致CHS反应的明显缺陷， 以及促进皮肤肿瘤生长。我们还表明，Rosig治疗阻断UV-IS和抑制皮肤 在免疫活性但非免疫缺陷小鼠宿主中的肿瘤生长。我们推测， 激活至少部分通过其反抑制信号传导的能力来抑制紫外线诱导的皮肤癌形成 参与UV-IS的途径。特别是，我们发现PPAR γ反式抑制一种叫做肿瘤坏死的蛋白质， 一种以全长跨膜形式和可溶性蛋白水解裂解形式存在的α因子（TNF-α） form.我们认为跨膜形式（tmTNF-α）主要参与免疫抑制。因此，在本发明中， PPAR γ配体可能被证明是有用的长期化学预防剂，可以促进免疫介导的免疫抑制。 清除皮肤癌高危个体的新生皮肤肿瘤。最后，最近的研究表明， 放射治疗，像紫外线，也促进全身免疫抑制，通过其诱导的能力， 氧化应激我们认为，反式抑制性的过氧化物酶体增殖物激活受体γ配体将逆转这种免疫抑制， 促进所谓的远位效应。这种远位效应导致肿瘤的抗肿瘤反应， 在放射治疗领域之外。虽然自发性远位效应很少发生， 促进免疫反应的努力可以使这种反应变得司空见惯。我们建议 反式抑制性PPAR γ配体将与放射治疗协同作用以促进远位效应。审查 根据我们的假设，研究将分为以下三个具体目标（SA）： SA#1：确定表皮PPAR γ是否通过跨膜TNF-α调节CHS反应 （tmTNF-α）而不是可溶性TNF-α（solTNF-α）。 SA#2：确定不同的PPAR γ配体诱导PPAR γ特异性反式阻遏的能力， 体外和体内UVB诱导NF-κ B活化和TNF-α产生。我们将把这个 具有逆转UV诱导的CHS反应抑制的能力。 SA#3：确定反式抑制性PPAR γ配体是否促进抗肿瘤免疫应答 单独或在外部束放射治疗之后。 这些研究将证明反式抑制性PPAR γ配体依赖性信号在 调节抗肿瘤免疫应答。它还将提供机制的见解，如何过氧化物酶体增殖物激活受体γ激活 抑制肿瘤发生和促进抗肿瘤免疫应答的作用， 反式抑制性PPAR γ配体作为化学预防剂或作为当前放射治疗的辅助治疗。