It is now well recognized that solid tumor progression is accompanied by the induction and maintenance of tumor antigen-specific T-cell tolerance through mechanisms akin to those that regulate responses to self-antigens. Unfortunately, this emerging view of tumor immunity has also raised the bar for cancer immunotherapy, since the barrier imposed by immune tolerance must be broken in order for the immune system to recognize and eliminate solid tumors expressing mainly """"""""self"""""""". Given these sobering implications, the study of immunological tolerance, its establishment and maintenance has remained the central focus of our laboratory for the past several years. The elucidation of the cellular and molecular mechanisms involved in the decision leading to immune activation versus immune tolerance represents a critical step not only to better understand the immune system, but also to identify potential targets to overcome the remarkable barrier that immune tolerance has imposed to cancer immunotherapy. The tools and experimental models developed in the last several years will be used to systematically pursue the overall goal of this project, which is to understand the mechanisms by which Stat3 signaling in bone marrow derived APCs influence the functional outcome of antigen-specific CD4 (Specific Aim 1) and CD8 T-cells (Specific Aim 2). Furthermore, in experimental models with model tumor antigens as well as true self/tumor antigens we will evaluate whether novel strategies targeting Stat3 signaling in APCs might overcome immune tolerance and enhance the efficacy of cancer vaccines (Specific Aim 3). The knowledge to be gained in this endeavor will provide the appropriate platform for future integration of novel therapeutic approaches targeting tolerogenic mechanisms in humans with already existing active immunotherapy strategies against solid tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA087583-06
Application #
7084545
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Muszynski, Karen
Project Start
2000-07-01
Project End
2010-04-30
Budget Start
2006-06-01
Budget End
2007-04-30
Support Year
6
Fiscal Year
2006
Total Cost
$250,692
Indirect Cost
Name
H. Lee Moffitt Cancer Center & Research Institute
Department
Type
DUNS #
139301956
City
Tampa
State
FL
Country
United States
Zip Code
33612
Cheng, Fengdong; Lienlaf, Maritza; Perez-Villarroel, Patricio et al. (2014) Divergent roles of histone deacetylase 6 (HDAC6) and histone deacetylase 11 (HDAC11) on the transcriptional regulation of IL10 in antigen presenting cells. Mol Immunol 60:44-53
Cheng, Fengdong; Lienlaf, Maritza; Wang, Hong-Wei et al. (2014) A novel role for histone deacetylase 6 in the regulation of the tolerogenic STAT3/IL-10 pathway in APCs. J Immunol 193:2850-62
Cheng, Fengdong; Wang, Hongwei; Horna, Pedro et al. (2012) Stat3 inhibition augments the immunogenicity of B-cell lymphoma cells, leading to effective antitumor immunity. Cancer Res 72:4440-8
Wang, Hongwei; Cheng, Fengdong; Woan, Karrune et al. (2011) Histone deacetylase inhibitor LAQ824 augments inflammatory responses in macrophages through transcriptional regulation of IL-10. J Immunol 186:3986-96
Brayer, Jason; Cheng, Fengdong; Wang, Hongwei et al. (2010) Enhanced CD8 T cell cross-presentation by macrophages with targeted disruption of STAT3. Immunol Lett 131:126-30
Vicente-Suarez, Ildelfonso; Brayer, Jason; Villagra, Alejandro et al. (2009) TLR5 ligation by flagellin converts tolerogenic dendritic cells into activating antigen-presenting cells that preferentially induce T-helper 1 responses. Immunol Lett 125:114-8
Villagra, Alejandro; Cheng, Fengdong; Wang, Hong-Wei et al. (2009) The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance. Nat Immunol 10:92-100
Horna, Pedro; Sotomayor, Eduardo M (2007) Cellular and molecular mechanisms of tumor-induced T-cell tolerance. Curr Cancer Drug Targets 7:41-53
Vicente-Suarez, Ildefonso; Takahashi, Yoshinori; Cheng, Fengdong et al. (2007) Identification of a novel negative role of flagellin in regulating IL-10 production. Eur J Immunol 37:3164-75
Horna, Pedro; Cuenca, Alex; Cheng, Fengdong et al. (2006) In vivo disruption of tolerogenic cross-presentation mechanisms uncovers an effective T-cell activation by B-cell lymphomas leading to antitumor immunity. Blood 107:2871-8

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