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

PPARγ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

基本信息

批准号：
10450626
负责人：
RAYMOND L KONGER
金额：
--
依托单位：
RLR VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10450626
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 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 military veteran neoplastic cell pre-clinical response rosiglitazone side effect tumor tumor growth tumorigenesis ultraviolet

项目摘要

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.

皮肤癌主要是由阳光暴露于环境紫外线（UV）引起的。我们已经表明在小鼠表皮（PPARG - / - EPI小鼠）表皮中，过氧化物体增生剂激活受体伽马（PPARγ）的丧失促进紫外线诱导的皮肤癌的形成。我们还表明PPARγ激动剂罗斯列酮（Rosig）保护小鼠免受皮肤癌的形成。对PPARγ配体分类的历史方法是它们通过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，激活和抑制反式激活的PPARγ配体已证明表现出抗肿瘤活性。这引起了关于PPARγ的抗肿瘤作用的混乱。但是，一些PPARγ配体也表现出通过称为明显不同的机制抑制其他基因表达的能力 “变形”。我们假设PPARγ配体依赖性的转化，而不是反式激活，是PPARγ抗肿瘤活性的关键。紫外线抑制T细胞介导的接触超敏反应（CHS）反应以及抗肿瘤免疫复杂（称为UV诱导的免疫抑制（UV-IS））。紫外线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。我们表明损失表皮PPARγ产生免疫抑制状态，导致CHS反应中明显缺陷为以及增强的皮肤肿瘤生长。我们还表明Rosig治疗会阻止紫外线并抑制皮肤免疫能力的肿瘤生长，但没有免疫缺陷的小鼠宿主。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由于其转化信号传导的能力紫外线涉及的途径。特别是，我们表明PPARγ会变形一种称为肿瘤坏死的蛋白质因子α（TNF-α）作为全长跨膜形式和固体蛋白水解裂解而存在形式。我们提出，跨膜形式（TMTNF-α）主要参与免疫抑制。那， PPARγ配体可能被证明可作为长期化学预防剂，可以促进免疫介导的皮肤癌高风险的个体中新生皮肤肿瘤的清除。最后，最近的研究表明这种放射疗法（如紫外线）也通过诱导其能力来促进系统性免疫抑制氧化应激。我们提出，转化PPARγ配体将逆转这种免疫抑制作用，并且促进所谓的脱离潜入效应。这种脱离作用导致肿瘤中的抗肿瘤反应在辐射处理领域之外。尽管赞成的脱离潜在影响很少发生，但存在证据促进免疫反应的努力可以使得这种反应司空见惯。我们提出了这一点透射PPARγ配体将与放射疗法一起起作用，以促进潜在的效果。检查我们的假设，研究将分为以下三个特定目标（SA）： SA＃1：确定表皮PPARγ是否通过跨膜TNF-α调节CHS响应（TMTNF-α）而不是固体TNF-α（Soltnf-α）。 SA＃2：确定潜水员PPARγ配体诱导PPARγ特异性转化的能力 UVB诱导的NF-κB激活和体内的TNF-α产生。我们将关联一下逆转录活性具有反向紫外线诱导的CHS响应抑制的能力。 SA＃3：确定转换PPARγ配体是否促进了抗肿瘤免疫反应单独或遵循外梁辐射疗法。这些研究将证明反应pPARγ配体依赖性信号在中的重要性调节抗肿瘤免疫反应。它还将提供有关PPARγ如何激活的机械洞察力抑制肿瘤发生并促进抗肿瘤免疫调查的作用，并为使用提供理由作为化学预防剂或当前放射疗法的辅助性的变性PPARγ配体的。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Evidence for a non-stochastic two-field hypothesis for persistent skin cancer risk.

DOI：
10.1038/s41598-020-75864-2
发表时间：
2020-11-05
期刊：
Scientific reports
影响因子：
4.6
作者：
Konger RL;Ren L;Sahu RP;Derr-Yellin E;Kim YL
通讯作者：
Kim YL

Epidermal PPARγ Is a Key Homeostatic Regulator of Cutaneous Inflammation and Barrier Function in Mouse Skin.

DOI：
10.3390/ijms22168634
发表时间：
2021-08-11
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Konger RL;Derr-Yellin E;Zimmers TA;Katona T;Xuei X;Liu Y;Zhou HM;Simpson ER Jr;Turner MJ
通讯作者：
Turner MJ

Evidence that peroxisome proliferator-activated receptor γ suppresses squamous carcinogenesis through anti-inflammatory signaling and regulation of the immune response.

有证据表明过氧化物酶体增殖物激活受体γ通过抗炎信号传导和免疫反应调节抑制鳞状细胞癌发生。