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Epigenetic regulation of metabolic stress pathways in melanoma infiltrating lymphocytes- Resubmission

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Epigenetic regulation of metabolic stress pathways in melanoma infiltrating lymphocytes Unleashing antitumor lymphocytes through checkpoint inhibition and adoptive cell therapies are incredibly promising strategies to fight metastatic melanoma. T cell adoptive therapies have shown success in patients that have failed checkpoint inhibitor therapies. The tumor-infiltrating lymphocytes (TIL) in adoptive therapy face a host of stresses as they encounter the tumor microenvironment including hypoxic conditions, glucose restriction, and immune suppression - all of which these cells must overcome to function therapeutically. Although it is known that epigenetic mechanisms play an important role in lymphocyte activation, the mechanisms these cells might use to adapt to the extreme conditions of the solid tumor environment are not well understood. The complete tumor regression rates for adoptive T cell therapy for melanoma are 10-20%; thus, new approaches to combat epigenetic immunomodulation are needed for adoptive cell therapies to reach their full potential. The methyltransferase EZH2 (Enhancer of Zeste Homolog 2) is a histone-modifying enzyme that has been shown to be rapidly induced during lymphocyte activation and a target of glucose deprivation in the melanoma microenvironment. The central hypothesis of this work is that the histone methyltransferase EZH2 protects TILs from metabolic stress-induced apoptosis. The following aims will be used to test this hypothesis: Aim1: Define changes in the histone epigenetic landscape of lymphocytes during EZH2 inhibition. Aim 2: Define the mechanism(s) by which loss of H3K27me3 sensitizes lymphocytes to metabolic stress. Aim 3: Demonstrate the therapeutic potential of EZH2 over-expression in tumor-specific lymphocytes. At the end of this study, I feel strongly that a novel mechanism will be defined for protection of lymphocytes during metabolic stress. Additionally, I intend to devise a novel approach for protecting lymphocytes from metabolic immunosuppression. I have assembled a mentoring team of leaders in epigenetics, cancer immunology, and proteomics that will facilitate this unique and rigorous training, preparing me to pursue a career as an independent academic scientist.

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