Tumor-specific T cell tolerance represents one of the major challenges in cancer immunotherapy. To elicit effective anti-tumor immunity, it is necessary to develop immunotherapeutic strategies capable of overcoming T cell tolerance. In a murine model of A20 lymphoma, we have demonstrated that tumor-specific CDS tolerance is mediated by CD4+CD25+ regulatory T (TReg) cells and that reversal of established TReg cell mediated tumor-specific CDS tolerance by tumor vaccines depends on sustained Toll-like receptor (TLR) signals of innate immunity in vivo. This can be achieved by virus-based vaccines that can provide TLR signals intrinsically or mature DC vaccines with co-administration of a TLR ligand. More importantly, provision of TLR signals significantly enhances the efficacy of tumor vaccines in treating pre-established A20 lymphoma, suggesting an essential role of TLR signals in cancer immunotherapy. In this application, we will investigate the mechanisms underlying TLR-dependent reversal of TReg cell-mediated tumor-specific CDS tolerance in vivo. Specifically, we will pursue the following five aims: 1) To determine if reversal of TReg cell-mediated tumor-specific CDS tolerance in vivo by vaccinia virus vs. adenovirus vaccines is mediated through distinct TLR pathways; 2) To delineate the role of pro-inflammatory cytokines IL-6, IL-12 and/or IL-1 in reversal of TReg cell-mediated tumor-specific CDS tolerance in vivo; 3)To assess the role of Type I interferons (IFNs) in overcoming TReg cell-mediated tumor-specific CD8 tolerance in vivo; 4) To investigate the role of glucocorticoid-induced TNF receptor family-related protein (GITR) and GITR ligand interaction in breaking TReg cell-mediated tumor-specific CDS tolerance in vivo; 5) To evaluate the efficacy of tumor vaccines with TLR signals in treating pre-established A20 lymphoma. The outcome of these studies should have significant impact on the design of effective immunotherapeutic strategies for treating cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA111807-03
Application #
7238857
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Welch, Anthony R
Project Start
2005-09-01
Project End
2010-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
3
Fiscal Year
2007
Total Cost
$288,390
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Novy, Patricia; Huang, Xiaopei; Leonard, Warren J et al. (2011) Intrinsic IL-21 signaling is critical for CD8 T cell survival and memory formation in response to vaccinia viral infection. J Immunol 186:2729-38
Brandstadter, Joshua D; Yang, Yiping (2011) Natural killer cell responses to viral infection. J Innate Immun 3:274-9
Sanchez, Ana M; Yang, Yiping (2011) The role of natural regulatory T cells in infection. Immunol Res 49:124-34
Martinez, Jennifer; Huang, Xiaopei; Yang, Yiping (2010) Direct TLR2 signaling is critical for NK cell activation and function in response to vaccinia viral infection. PLoS Pathog 6:e1000811
Huang, Xiaopei; Yang, Yiping (2010) Targeting the TLR9-MyD88 pathway in the regulation of adaptive immune responses. Expert Opin Ther Targets 14:787-96
Martinez, Jennifer; Huang, Xiaopei; Yang, Yiping (2010) Toll-like receptor 8-mediated activation of murine plasmacytoid dendritic cells by vaccinia viral DNA. Proc Natl Acad Sci U S A 107:6442-7
Zhu, Jiangao; Huang, Xiaopei; Yang, Yiping (2009) The TLR9-MyD88 pathway is critical for adaptive immune responses to adeno-associated virus gene therapy vectors in mice. J Clin Invest 119:2388-98
Quigley, Michael; Martinez, Jennifer; Huang, Xiaopei et al. (2009) A critical role for direct TLR2-MyD88 signaling in CD8 T-cell clonal expansion and memory formation following vaccinia viral infection. Blood 113:2256-64
Huang, Xiaopei; Yang, Yiping (2009) Innate immune recognition of viruses and viral vectors. Hum Gene Ther 20:293-301

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