Regulatory T cells (Tregs) play a major role in establishing and maintaining immune tolerance in tissues, with a predilection for epithelial barriers such as skin. Augmenting the function of these cells has significant potential to treat cutaneous inflammation and inhibiting the function of these cells may prove efficacious in treating cutaneous malignancies. We recently characterized a unique population of Tregs in both murine and human skin, termed memory Tregs (mTreg). These cells are highly activated suppressors that are stably maintained in skin for relatively long periods of time and have enhanced functional capacity to attenuate inflammation. The underlying theme of this proposal is to functionally dissect the dominant pathways utilized by mTregs in skin and develop novel strategies to specifically augment or inhibit the function of these cells in a tissue-specific fashion. To achieve this goal, we will utilize novel technological advances in our ability to disset the function of immune cells in human skin in vivo. This is a high-risk high-reward proposal with the potential for direct translation to human disease. Its innovativeness stems from the fact that we will utilize newly established transgenic mouse model systems to inform experiments in humanized mice, enabling us to effectively and efficiently translate findings from mice to humans. On a basic level, we will gain critical mechanistic insight as to how mTregs function in skin and, on a translational level, we will exploit this knowledge to develop new treatment strategies for inflammatory or malignant skin disease.
Local tissue-specific therapies that enhance the body's immune system have the potential to resolve inflammation and eradicate cancer with minimal systemic side effects. The overall goal of this grant application is to understand how the immune system functions in the skin. Using this knowledge we will develop new strategies to enhance the skin's immune system to treat chronic inflammatory skin diseases and skin cancer.
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|Tumeh, Paul C; Hellmann, Matthew D; Hamid, Omid et al. (2017) Liver Metastasis and Treatment Outcome with Anti-PD-1 Monoclonal Antibody in Patients with Melanoma and NSCLC. Cancer Immunol Res 5:417-424|
|Schulman, Joshua M; Pauli, Mariela L; Neuhaus, Isaac M et al. (2016) The distribution of cutaneous metastases correlates with local immunologic milieu. J Am Acad Dermatol 74:470-6|
|Daud, Adil I; Loo, Kimberly; Pauli, Mariela L et al. (2016) Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma. J Clin Invest 126:3447-52|
|Rosenblum, Michael D; Way, Sing Sing; Abbas, Abul K (2016) Regulatory T cell memory. Nat Rev Immunol 16:90-101|
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