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

Public Health Relevance

The proposed research will explore how HIF-1, an integrator of metabolic signals, controls the balance between T cell subsets both in vitro and in vivo. Importantly, this study will determine the therapeutic potential of HIF-1 targeting as a therapeuti strategy for altering cancer immunity. While we focus specifically on models of colitis and colitis associated colon cancer as well as implantable melanoma, numerous immune mediated pathologies stand to benefit from novel and potent agents capable of reversing the nature of harmful immune responses. Therefore, if our hypotheses are supported by the proposed studies the strategy of HIF-1 targeting will likely be advanced to clinical trials with enthusiasm. PUBLIC HEALTH RELEVANCE: The proposed research will expand our understanding of the mechanisms through which T cell fate decisions are affected by metabolic cues via HIF-1 and determine the translational relevance of targeting this molecule as means of promoting cancer immunity. The results of these studies may provide the basis for future clinical testing of this immune modulating strategy and will further define several aspects of T cell differentiation and the interface between immune cells and the unique cancer microenvironment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI099300-02
Application #
8581340
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Ferguson, Stacy E
Project Start
2012-11-15
Project End
2017-10-31
Budget Start
2013-11-01
Budget End
2014-10-31
Support Year
2
Fiscal Year
2014
Total Cost
$364,500
Indirect Cost
$139,500
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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van Loosdregt, Jorg; Fleskens, Veerle; Fu, Juan et al. (2013) Stabilization of the transcription factor Foxp3 by the deubiquitinase USP7 increases Treg-cell-suppressive capacity. Immunity 39:259-71