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

• 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
• 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

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.

皮肤癌是由阳光的环境紫外线（UV）导致的。 小鼠表皮中过氧化物酶体增殖物激活受体伽马（PPARγ）的丧失（PPARG - / - EPI小鼠） 促进紫外线诱导的皮肤癌。 （Rosig）保护小鼠免受皮肤癌的形成。 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。 激活和抑制反式激活的PPARγ配体已经表现出抗肿瘤活性。 这引起了PPARγ的抗肿瘤作用的困惑。 表现出通过称为不同的机制抑制其他基因表达的能力 “变形”。 是PPARγ抗肿瘤活性的关键。 反应以及抗肿瘤的免疫反应（称为UV诱导的免疫选择（UV-IS）） 我们可能通过促进对肿瘤特异性抗原的耐受性来促进皮肤癌。 表皮PPARγ产生免疫性状态状态，导致CHS反应中明显缺陷 以及增强的皮肤肿瘤生长。 免疫胜任的肿瘤生长，而不是Imbistication小鼠宿主。 激活抑制紫外线诱导的皮肤癌的形成，至少部分通过超压子信号传导 尤其是紫外线的途径。 因子α（TNF-α）作为全长跨膜形式和可溶性蛋白水解裂解 我们提出的是，跨膜形式（TMTNF-α）主要参与免疫。 PPARγ配体可能被证明可作为长期化学预防剂，可促进免疫介导的 最终的研究表明，在高风险的个体中清除皮肤肿瘤。 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。 促进所谓的脱落效应。 在辐射治疗领域之外。 促进免疫反应的努力可以使这一反应使得我们提出这一点 具有活性的跨性别PPARγ配体在附近促进脱落作用 我们的假设，研究将分为以下三个特定AM（SA）： SA＃1：确定表皮PPARγ是否通过跨膜TNF-α调节CHS响应 （TMTNF-α），而不是可溶性TNF-α（soltnf-α）。 SA＃2：确定各种pparands的多种多样，以诱导PPARAN-S-S-S-S-S-S-S-Spacific Transpression UVB诱导的NF-κB激活和TNF-α在体外和体内产生。 具有反向紫外线抑制CHS响应的能力的反表示活性。 SA＃3：确定Trepsrepressive Pparands是否促进了抗肿瘤免疫反应 单独或遵循外梁辐射疗法。 这些研究将证明变性PPARAN配体依赖性信号传导的重要性 调节抗肿瘤免疫反应。 抑制肿瘤发生并促进抗肿瘤免疫反应的作用 作为化学预防剂或当前放射疗法的相邻剂的变性pparands的。

项目成果

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。

• DOI: 10.1002/mc.23041
• 发表时间: 2019
• 期刊: Molecular carcinogenesis
• 影响因子: 4.6
• 作者: Ren,Lu;Konger,RaymondL
• 通讯作者: Konger,RaymondL