Translational Science: Cancer as a systemic disease (15-CA-115): Although tumor vaccines can induce CD4 helper and CD8 cytotoxic response against tumor antigens, they have been largely ineffective in causing tumor regression in the clinic. This is because the tumor cells acquire many mechanisms to evade the immune surveillance program of the host. Foxp3+CD4+CD25+Treg-mediated immune suppression has emerged as one of the crucial tumor immune evasion mechanisms and main obstacle of successful tumor immunotherapy. Most malignant cells including prostate cancer cells secret large amounts of TGF-? and has been shown to convert the effector T cells into tumor antigen specific Tregs by inducing Foxp3 expression. Such tumor induced Tregs not only suppress the priming and effector function of anti-tumor effector cells but also form a broad network of self-amplifying immunosuppressive network. Therefore, overcoming tumor induced expansion and de novo generation of Tregs is critically important for the design of effective immunotherapeutic strategies for successful cancer treatment. We have demonstrated a critical role of TGF-? inducible early gene-1 (TIEG1) in the transcriptional regulation of Foxp3 in CD4T cells treated with TGF-?. E3 ligase Itch-mediated monoubiquitination is essential for nuclear translocation, and transcriptional activation of TIEG1. However, in transient overexpression systems Itch targets TIEG1 for both mono and polyubiquitination. Our preliminary studies suggest that IL-6 which inhibits TGF-? induced Foxp3 expression induces proteasomal degradation of TIEG1 possibly through polyubiquitination. Tyk2-mediated phosphorylation of TIEG1 seems to act as a recognition signal for polyubiquitination of TIEG1. Therefore, we hypothesize that Itch targets TIEG1 differentially for mono and polyubiquitination when the CD4T cells are stimulated with TGF-? or IL-6 and regulates its activation and degradation. Despite the growing body of data on the role of Foxp3 in Treg development and function, how Foxp3 transcription is regulated is not clear. We have identified consensus NFAT and TIEG1 binding sites adjacent to each other on Foxp3 promoter. Since, most transcription factors work cooperatively with other factors binding in close proximity we hypothesize that NFAT and TIEG1 interact on Foxp3 promoter and regulate chromatin remodeling and Foxp3 expression. A clear understanding of molecular combinations and cross-talks that imprint Foxp3 transcription in CD4T cells will aid in designing strategies to disrupt the inhibitory network of Tregs in tumor microenvironment. Using prostate cancer TRAMP-C2 cells which secrete large amount of TGF-?, we will analyze the effect of TIEG1 deficiency on Treg development and tumor progression. Since TIEG1 does not effect nTreg development in the thymus, targeting TIEG1 is an appealing strategy to block the de novo induction of Tregs. Such a strategy is expected to eliminate most potent tumor specific Tregs that inhibit anti-tumor immune response without the risk of triggering autoimmunity.

Public Health Relevance

The application is in response to the Recovery Act Challenge Grant;Research Area: Translational Science Topic;(15-CA-115), Cancer as a systemic disease. This innovative application proposes to study the role of TGF-? inducible early gene-1(TIEG1) in the induction of Foxp3+Tregs by TGF-? secreted from tumor cells. The results obtained from these studies are expected gain significant new insights to maximize current immunotherapeutic approaches. In addition it complies with the spirit of the Challenge Grant as it will necessitate the hiring of new employees, especially in Detroit, Michigan which suffers from the highest unemployment rate in the country.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
NIH Challenge Grants and Partnerships Program (RC1)
Project #
1RC1CA146576-01
Application #
7830845
Study Section
Special Emphasis Panel (ZRG1-OTC-K (58))
Program Officer
Mccarthy, Susan A
Project Start
2009-09-30
Project End
2011-08-31
Budget Start
2009-09-30
Budget End
2010-08-31
Support Year
1
Fiscal Year
2009
Total Cost
$499,405
Indirect Cost
Name
Wayne State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Ahmed, Neesar; Zeng, Minghui; Sinha, Indrajit et al. (2011) The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammation. Nat Immunol 12:1176-83
Peng, Dong-Jun; Zeng, Minghui; Muromoto, Ryuta et al. (2011) Noncanonical K27-linked polyubiquitination of TIEG1 regulates Foxp3 expression and tumor growth. J Immunol 186:5638-47
Venuprasad, K; Poojary, K Venuprasad; Kong, Yi-Chi M et al. (2010) Control of Th2-mediated inflammation by regulatory T cells. Am J Pathol 177:525-31
Venuprasad, K (2010) Cbl-b and itch: key regulators of peripheral T-cell tolerance. Cancer Res 70:3009-12