Metabolic regulation of T cell fate and tumor immunity

Johns Hopkins University, Baltimore MD

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Abstract

DESCRIPTION (provided by applicant): Immunotherapy, which focuses on augmenting host immunity against tumor-associated antigens, represents an important means to treat cancer that is yielding clinical success. Successful manipulation of T cell responses requires understanding how particular T cell subsets influence cancer development and growth. For example, Th1 and Th17 cells can augment tumorigenesis. Treg cells can block anti-tumor immune responses and thus represents one of the main obstacles to successful tumor immunotherapy. While Tregs are recognized as tumor supporting cells, the relationship between Th17 cells and tumor immunity has been controversial. A major unappreciated element in T cell fate decisions is the metabolic environment. As part of an effort to study the metabolic regulation of T cell differentiation decisions, we have discovered that hypoxia inducible factor 1 (HIF-1) plays a critical role in driving the Th17 response. Further preliminary results suggest that lack of this molecule results in reduced tumor initiation and progression. In this proposal, we aim to: (1) further dissect the role of HIF-1 in Th17 development. We will address the breadth, and particular facets of HIF-1's contribution to the Th17 lineage. We will also touch on the suitability of HIF-1 as a therapeutic target in humans; (2) we will explore the role of HIF-1 in regulating the Th17 and Treg responses in inflammation-induced carcinogenesis and cancer progression; (3) we will subsequently use these in vivo cancer models to test the therapeutic potential of HIF-1 targeting. In these studies mice will be treated with the HIF-1 inhibitors, Digoxin and Acriflavine and we will evaluate the ability of these compounds to impede tumor growth either alone or in concert with Treg depletion. Such a strategy is expected to have potent anti-tumor effects as it should, given our preliminary data and past results, simultaneously sabotage two major tumor- promoting immune cell populations