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.

皮肤癌主要是由环境中的紫外线(UV)暴露在阳光下引起的。我们已经证明了 PPARγ在小鼠(PPARG-/-EPI小鼠)表皮中的缺失 促进紫外线诱导的皮肤癌的形成。我们还证明了PPARγ激动剂罗格列酮 (Rosig)保护小鼠免受皮肤癌的形成。历史上对PPARγ配体的分类方法是 他们通过一种称为反式激活的过程激活与脂肪生成相关的基因的能力。然而， 激活和抑制反式激活的PPARγ配体已被证明具有抗肿瘤活性。 这造成了人们对PPARγ抗肿瘤作用的困惑。然而，一些PPARγ配体也 表现出通过一种截然不同的机制抑制其他基因表达的能力 “反压抑”。我们假设PPARγ依赖于配体的反式抑制，而不是反式激活， 是PPARγ抗肿瘤活性的关键。紫外线抑制T细胞介导的接触性超敏反应 以及抗肿瘤免疫反应(称为紫外线诱导的免疫抑制(UV-IS))。UV-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。我们显示了损失的 表皮PPARγ产生免疫抑制状态，导致CHS反应明显缺陷，如 以及促进皮肤肿瘤的生长。我们还表明，Rosig治疗可以阻止紫外线-IS并抑制皮肤 肿瘤在免疫活性的小鼠宿主中生长，但不在免疫缺陷的小鼠宿主中生长。我们假设PPARγ 激活抑制紫外线诱导的皮肤癌的形成至少部分是通过其转录抑制信号的能力 参与UV-IS的通路。特别是，我们发现PPARγ转录了一种叫做肿瘤坏死的蛋白质。 因子α(肿瘤坏死因子-α)，既以全长跨膜形式存在，又以可溶性蛋白水解性切割形式存在 形式。我们认为跨膜形式(tmTNF-α)主要参与免疫抑制。因此， PPARγ配体可能被证明是有用的长期化学预防药物，将促进免疫介导性 清除皮肤癌高危人群中的新生皮肤肿瘤。最后，最近的研究表明 与紫外线一样，放射疗法也通过诱导免疫抑制来促进全身免疫抑制 氧化应激。我们认为，反式抑制的PPARγ配体将逆转这种免疫抑制，并 促进所谓的范围外效应。这种非局部性效应导致肿瘤产生抗肿瘤反应， 在放射治疗领域之外。虽然自发的非局域效应很少发生，但有证据表明 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 反式抑制的PPARγ配体将与放射治疗协同作用，以促进非局部效应。检视 根据我们的假设，这些研究将分为以下三个具体目标(SA)： SA#1：确定表皮PPARγ是否通过跨膜肿瘤坏死因子-α调节CHS反应 (tm肿瘤坏死因子-α)而不是可溶性肿瘤坏死因子-α(可溶性肿瘤坏死因子-α)。 SA#2：确定不同的PPARγ配体诱导PPARγ特异性反转录的能力 中波紫外线在体内外均可诱导NF-κB活化和产生肿瘤坏死因子α。我们将把这一点联系起来 具有逆转紫外线诱导的CHS反应抑制作用的反式抑制活性。 SA#3：确定反式抑制PPARγ配体是否促进抗肿瘤免疫反应 单独或在体外放射治疗后。 这些研究将证明反式抑制PPARγ配体依赖的信号转导在 调节抗肿瘤免疫反应。它还将提供对PPARγ激活方式的机械性见解 抑制肿瘤形成和促进抗肿瘤免疫反应的作用并为其使用提供理论基础 将反式抑制型PPARγ配体用作化学预防药物或作为当前放射治疗的辅助手段。