In spite of the significant advances made in early diagnosis and treatment of cancer, the majority of solid tumors are still incurable with the treatments currently available. Several immune-enhancing strategies have been therefore developed in experimental models, and although they have been very successful in """"""""protecting"""""""" against a subsequent tumor challenge, they have often failed when given shortly after the solid tumor is established. Recently, utilizing T cell receptor (TCR) transgenic mice specific for a model tumor antigen expressed on a Renal cell carcinoma (RencaHA), we have found that antigen specific CD4+ T cells are rendered anergic early during tumor progression. The induction of T cell unresponsiveness occurs in the absence of tumor invasion to the lymphoid organs, suggesting mechanism(s) that are independent of a direct tumor-CD4+ T cell interaction, Indeed, using parent-into-Fl bone marrow chimeras we have unambiguously demonstrated that tumor antigen processing and presentation by bone marrow derived antigen-presenting cells (APCs) is the dominant mechanism underlying the development of tumor antigen specific T cell tolerance (""""""""cross-tolerance""""""""). Importantly, the induction of this state of T-cell unresponsiveness is associated with the loss of therapeutic tumor-cell based vaccine efficacy pointing therefore, to tumor induced antigen-specific T-cell tolerance as a critical barrier in the design of an effective cancer immunotherapy. Therefore, the overall goal of this proposal is to utilize this model of solid tumor-induced tolerance for elucidating the mechanism(s) at the APC level that are central in the decision leading to activation versus tolerance of antigen-specific T cells. Furthermore, we will determine whether decreasing the tumor burden (by surgery and/or radiation treatment) may result in reversal -or not- of tumor-induced tolerance. Most importantly - in terms of clinical relevance - we will explore whether immunotherapeutic strategies aimed to enhance APCs function (treatment with CD4O activating antibodies) and/or strategies aimed to enhance T cell function (blocking T-cell inhibitory signals with anti-CTLA4 blocking antibodies) may break this state of T cell unresponsiveness. The knowledge to be gained in this endeavor will shed light not only on the basic biology of host-tumor interaction, but it will provide us with the therapeutic tools needed for safely break solid tumors-induced tolerance, and achieving the long-elusive success of cancer immunotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA087583-01A1
Application #
6327307
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Yovandich, Jason L
Project Start
2001-04-01
Project End
2005-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
1
Fiscal Year
2001
Total Cost
$158,839
Indirect Cost
Name
University of South Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
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
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; Sotomayor, Eduardo M (2007) Cellular and molecular mechanisms of tumor-induced T-cell tolerance. Curr Cancer Drug Targets 7:41-53
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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