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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.

皮肤癌主要是由暴露在阳光中的环境紫外线（UV）引起的。我们已经证明了

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。