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

Rlr Va Medical Center, Indianapolis IN

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Abstract

Skin cancer is primarily caused by environmental ultraviolet (UV) exposure from sunlight. We have shown that loss of peroxisome proliferator activated receptor gamma (PPAR?) in the epidermis of mice (Pparg-/-epi mice) promotes UV-induced skin cancer formation. We have also shown that the PPAR? agonist rosiglitazone (Rosig) protects mice against skin cancer formation. The historical method for classifying PPAR? ligands is by their ability to activate genes associated with adipogenesis through a process called transactivation. However, PPAR? 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 PPAR?. However, some PPAR? ligands also exhibit the ability to suppress the expression of other genes through a distinctly different mechanism called ?transrepression?. We hypothesize that PPAR? ligand-dependent transrepression, rather than transactivation, is key to the anti-tumor activity of PPAR?. 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 PPAR? 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 PPAR? 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 PPAR? transrepresses a protein called tumor necrosis factor ? (TNF-?) that is present as both a full-length transmembrane form and a soluble proteolytically cleaved form. We propose that the transmembrane form (tmTNF-?) is primarily involved in immune suppression. Thus, PPAR? 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 PPAR? 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 PPAR? 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 PPAR? regulates CHS responses through transmembrane TNF-? (tmTNF-?) rather than soluble TNF-? (solTNF-?). SA#2: Determine the capacity of diverse PPAR? ligands to induce PPAR?-specific transrepression of UVB-induced NF-?B activation and TNF-? 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 PPAR? ligands promote anti-tumor immune responses either alone or following external beam radiation therapy. These studies will demonstrate the importance of transrepressive PPAR? ligand-dependent signaling in regulating anti-tumor immune responses. It will also provide mechanistic insight into how PPAR? activation acts to suppress tumorigenesis and promote anti-tumor immune responses and provide a rationale for the use of transrepressive PPAR? ligands as chemopreventive agents or as an adjunct to current radiotherapy.