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Identification and targeting of novel pathways modifying the epigenome of aged regulatory T cells in the tumor microenvironment

Cruz, Leilani and Rowell, Emily and Heidt, Analeah (2017) Identification and targeting of novel pathways modifying the epigenome of aged regulatory T cells in the tumor microenvironment. Damon Runyon Cancer Research Fellowship.

Abstract

Regulatory T (Tregs) cells are necessary for maintaining immunological tolerance. The way in which immunosenescence affects Treg biology is not well defined, but aged Tregs are noticeably altered in their immunological response. It is well established that the epigenetic landscape drastically changes during aging as a result of somatic mutations and compromised genomic stability. In a tumor microenvironment (TME), Tregs are enriched and dampen tumor-specific immune responses, thus facilitating tumor growth. As aging compromises proper Treg function and is a high risk for cancer development, we are proposing to investigate the impact of aging on Treg generation and function. We will utilize available preclinical syngeneic tumor models to study the impact of Tregs on tumor growth. Aim 1 will survey the changes in the epigenetic landscape of Tregs from young and old mice, both in vitro and in vivo in tumor-bearing animals. This dataset will be enhanced through detailed functional characterization and is key to establishing global changes in the epigenomic architecture in aged, tumor-infiltrating Tregs, the population that is most relevant to the typical human cancer patient. Aim 2 capitalizes on the strengths of GNF in compound and genomic screening and will allow us to specifically define the relevant enzymatic players responsible for chromatin modulation in the varied Treg populations followed by functional analysis. Collectively, our studies will contribute to the understanding of the impact of epigenetic modifying agents on tumor-infiltrating Tregs when used as part of anti-tumor immunotherapy.

Item Type: Article
Date Deposited: 26 Apr 2017 00:45
Last Modified: 26 Apr 2017 00:45
URI: https://oak.novartis.com/id/eprint/32455

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