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.
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.
|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|
|Sonpavde, Guru; Wang, Mingjun; Peterson, Leif E et al. (2014) HLA-restricted NY-ESO-1 peptide immunotherapy for metastatic castration resistant prostate cancer. Invest New Drugs 32:235-42|
|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|
|Li, Qingtian; Zou, Jia; Wang, Mingjun et al. (2014) Critical role of histone demethylase Jmjd3 in the regulation of CD4+ T-cell differentiation. Nat Commun 5:5780|
|Deng, Tuo; Lyon, Christopher J; Minze, Laurie J et al. (2013) Class II major histocompatibility complex plays an essential role in obesity-induced adipose inflammation. Cell Metab 17:411-22|
|Ajibade, Adebusola A; Wang, Helen Y; Wang, Rong-Fu (2013) Cell type-specific function of TAK1 in innate immune signaling. Trends Immunol 34:307-16|
|Tong, Yanzheng; Cui, Jun; Li, Qingtian et al. (2012) Enhanced TLR-induced NF-ýýB signaling and type I interferon responses in NLRC5 deficient mice. Cell Res 22:822-35|
|Wang, Helen Y; Wang, Rong-Fu (2012) Enhancing cancer immunotherapy by intracellular delivery of cell-penetrating peptides and stimulation of pattern-recognition receptor signaling. Adv Immunol 114:151-76|
|Cui, Jun; Li, Yinyin; Zhu, Liang et al. (2012) NLRP4 negatively regulates type I interferon signaling by targeting the kinase TBK1 for degradation via the ubiquitin ligase DTX4. Nat Immunol 13:387-95|
|Xia, Xiaojun; Cui, Jun; Wang, Helen Y et al. (2011) NLRX1 negatively regulates TLR-induced NF-?B signaling by targeting TRAF6 and IKK. Immunity 34:843-53|
Showing the most recent 10 out of 21 publications