Harnessing T cells to destroy human tumors is an attractive strategy that has met with only limited success. Among the reasons for this failure is that CD4+ T cells can differentiate to discrete subsets, one of which - CD4+ Treg cells - potently suppresses the CD4+ and CD8+ effector T cells. Although elevated percentages of Treg cells have been detected in many types of cancer, the origin of this subset of T cells in tumor microenvironment is poorly understood. Clearly, a better understanding of the origin and mechanisms of generation of CD4+ subsets would accelerate efforts to develop more effective cancer immunotherapy. The long-term goals of this proposal are to determine how Treg cells from CD4+ T cells and how Toll like receptor (TLR) signaling controls Treg cell function, and then to develop new strategies that might overcome immune suppression mediated by Treg cells, thus tipping the balance toward strong antitumor immunity. The central hypothesis of this application that tumor-reactive CD4+ T cells may be an important source of antigen-specific Treg cells generated after chronic tumor antigen stimulation is firmly grounded in the advances made during successful completion of R01 CA90327. New preliminary studies that includes the establishment of numerous CD4+ T cell lines/clones and hTLR8 transgenic mouse model, and the recent demonstration of CD4+ Treg cell functional reversal through TLR signaling, place us in an ideal position to undertake studies that will not only test this hypothesis, but will extend its predictions to possible immunotherapeutic applications as well.
Specific Aim 1 seeks to identify the origin and factors contributing to the generation of CD4+ Treg cells from effector/memory Th cells and to evaluate their suppressive function in vitro and in vivo.
Aim 2 will identify the signaling pathways and small molecule compounds that can be exploited to modulate Treg cell function. Ultimately in Aim 3, fundamental information regarding antigenic peptide stimulation of tumor-specific T cells and optimal methods of blocking Treg cell suppressive function will be incorporated into new cancer vaccine strategies and test in hTLR8 transgenic animal models. Successful completion of the proposed studies will provide new insights into the origin and regulation of CD4+ T cell subsets, especially Treg cells, and demonstrate the feasibility of boosting antitumor immunity by inhibiting the immunosuppressive function of antigen-specific Treg cells.

Public Health Relevance

Cancer immunotherapy is a promising therapy for cancer patients. In order to develop effective cancer vaccines, it is necessary to have a better understanding of the generation and suppressive mechanisms of CD4+ regulatory T cells and their function in antitumor immunity. This proposal seeks to understand how Treg cells are generated, to identify critical signaling pathways and small molecule drugs that control regulatory T cell function, and then to develop new strategies that might overcome immune suppression mediated by regulatory T cells, thus, tipping the balance toward strong antitumor immunity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA090327-06A2
Application #
7579685
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Howcroft, Thomas K
Project Start
2001-04-01
Project End
2013-11-30
Budget Start
2008-12-01
Budget End
2009-11-30
Support Year
6
Fiscal Year
2009
Total Cost
$309,164
Indirect Cost
Name
Baylor College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Ning, Bo; Zhao, Wei; Qian, Chen et al. (2017) USP26 functions as a negative regulator of cellular reprogramming by stabilising PRC1 complex components. Nat Commun 8:349
Jin, Shouheng; Tian, Shuo; Chen, Yamei et al. (2016) USP19 modulates autophagy and antiviral immune responses by deubiquitinating Beclin-1. EMBO J 35:866-80
Qin, Yunfei; Liu, Qingxiang; Tian, Shuo et al. (2016) TRIM9 short isoform preferentially promotes DNA and RNA virus-induced production of type I interferon by recruiting GSK3? to TBK1. Cell Res 26:613-28
Ning, Bo; Li, Wenyuan; Zhao, Wei et al. (2016) Targeting epigenetic regulations in cancer. Acta Biochim Biophys Sin (Shanghai) 48:97-109
Yang, Zhifen; Xian, Huifang; Hu, Jiajia et al. (2015) USP18 negatively regulates NF-?B signaling by targeting TAK1 and NEMO for deubiquitination through distinct mechanisms. Sci Rep 5:12738
Burchfield, Jana S; Li, Qingtian; Wang, Helen Y et al. (2015) JMJD3 as an epigenetic regulator in development and disease. Int J Biochem Cell Biol 67:148-57
Wu, Jian; Cai, Baowei; Sun, Wenxiang et al. (2015) Genome-wide Analysis of Host-Plasmodium yoelii Interactions Reveals Regulators of the Type I Interferon Response. Cell Rep 12:661-72
Wang, Mingjun; Yin, Bingnan; Wang, Helen Y et al. (2014) Current advances in T-cell-based cancer immunotherapy. Immunotherapy 6:1265-78
Cui, Jun; Song, Yanxia; Li, Yinyin et al. (2014) USP3 inhibits type I interferon signaling by deubiquitinating RIG-I-like receptors. Cell Res 24:400-16
Wu, Jian; Tian, Linjie; Yu, Xiao et al. (2014) Strain-specific innate immune signaling pathways determine malaria parasitemia dynamics and host mortality. Proc Natl Acad Sci U S A 111:E511-20

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