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

> **NIH VA I01** · RLR VA MEDICAL CENTER · 2020 · —

## Abstract

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 epiderma...

## Key facts

- **NIH application ID:** 9898276
- **Project number:** 5I01BX003762-04
- **Recipient organization:** RLR VA MEDICAL CENTER
- **Principal Investigator:** RAYMOND L KONGER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-04-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898276

## Citation

> US National Institutes of Health, RePORTER application 9898276, Regulation of cutaneous immune function and anti-tumor immune responses by PPARgamma-mediated transrepressive signaling (5I01BX003762-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898276. Licensed CC0.

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