The Role of Toll-Like Receptors in Cancer Immunotherapy

Summary

Principal Investigator: Yiping Yang
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2005-09-01 - 2010-04-30
more information: NIH RePORT

Top Publications

  1. pmc The development and function of memory regulatory T cells after acute viral infections
    Ana M Sanchez
    Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA
    J Immunol 189:2805-14. 2012
  2. pmc Intrinsic IL-21 signaling is critical for CD8 T cell survival and memory formation in response to vaccinia viral infection
    Patricia Novy
    Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA
    J Immunol 186:2729-38. 2011
  3. pmc Natural killer cell responses to viral infection
    Joshua D Brandstadter
    Molecular Cancer Biology Program, Duke University Medical Center, Durham, NC 27710, USA
    J Innate Immun 3:274-9. 2011
  4. pmc The role of natural regulatory T cells in infection
    Ana M Sanchez
    Department of Immunology, Duke University Medical Center, Box 103005, Durham, NC 27710, USA
    Immunol Res 49:124-34. 2011
  5. pmc Targeting the TLR9-MyD88 pathway in the regulation of adaptive immune responses
    Xiaopei Huang
    Duke University Medical Center, Department of Medicine, Durham, NC 27710, USA
    Expert Opin Ther Targets 14:787-96. 2010
  6. pmc Toll-like receptor 8-mediated activation of murine plasmacytoid dendritic cells by vaccinia viral DNA
    Jennifer Martinez
    Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
    Proc Natl Acad Sci U S A 107:6442-7. 2010
  7. pmc Direct TLR2 signaling is critical for NK cell activation and function in response to vaccinia viral infection
    Jennifer Martinez
    Department of Immunology, Duke University Medical Center, Durham, North Carolina, United States of America
    PLoS Pathog 6:e1000811. 2010
  8. pmc The TLR9-MyD88 pathway is critical for adaptive immune responses to adeno-associated virus gene therapy vectors in mice
    Jiangao Zhu
    Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA
    J Clin Invest 119:2388-98. 2009
  9. pmc Induction of type I IFN is required for overcoming tumor-specific T-cell tolerance after stem cell transplantation
    Ian Horkheimer
    Departments of Medicine, Duke University Medical Center, Durham, NC 2771, USA
    Blood 113:5330-9. 2009
  10. pmc Innate immune recognition of viruses and viral vectors
    Xiaopei Huang
    Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
    Hum Gene Ther 20:293-301. 2009

Scientific Experts

  • Yiping Yang
  • Xiaopei Huang
  • Jiangao Zhu
  • Jennifer Martinez
  • Michael Quigley
  • Ana M Sanchez
  • Patricia Novy
  • Joshua D Brandstadter
  • Ian Horkheimer
  • Warren J Leonard
  • Nelson J Chao

Detail Information

Publications19

  1. pmc The development and function of memory regulatory T cells after acute viral infections
    Ana M Sanchez
    Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA
    J Immunol 189:2805-14. 2012
    ..Our work reveals a memory Treg population that develops after acute viral infections and may help in the design of effective strategies to circumvent excessive immunopathological effects...
  2. pmc Intrinsic IL-21 signaling is critical for CD8 T cell survival and memory formation in response to vaccinia viral infection
    Patricia Novy
    Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA
    J Immunol 186:2729-38. 2011
    ..These results identify a critical role for intrinsic IL-21 signaling in CD8 T cell responses to an acute viral infection in vivo and may help design effective vaccine strategies...
  3. pmc Natural killer cell responses to viral infection
    Joshua D Brandstadter
    Molecular Cancer Biology Program, Duke University Medical Center, Durham, NC 27710, USA
    J Innate Immun 3:274-9. 2011
    ..We will then focus on the recruitment of activated NK cells to the site of infection as well as on NK cell effector mechanisms against virally infected cells...
  4. pmc The role of natural regulatory T cells in infection
    Ana M Sanchez
    Department of Immunology, Duke University Medical Center, Box 103005, Durham, NC 27710, USA
    Immunol Res 49:124-34. 2011
    ..Finally, we discuss the ways in which the T(Reg) function can be altered by invading pathogens and how these can be exploited to develop methods therapeutically to influence disease and vaccine outcomes...
  5. pmc Targeting the TLR9-MyD88 pathway in the regulation of adaptive immune responses
    Xiaopei Huang
    Duke University Medical Center, Department of Medicine, Durham, NC 27710, USA
    Expert Opin Ther Targets 14:787-96. 2010
    ..Recent advances also reveal a crucial role for TLRs in shaping adaptive immune responses, conferring a potential therapeutic value to their modulation in the treatment of diseases...
  6. pmc Toll-like receptor 8-mediated activation of murine plasmacytoid dendritic cells by vaccinia viral DNA
    Jennifer Martinez
    Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
    Proc Natl Acad Sci U S A 107:6442-7. 2010
    ..Collectively, our data are unique in demonstrating that TLR8 is required for sensing poly(A)/T-rich DNA in pDCs, and that murine TLR8 is functional in the context of a viral infection...
  7. pmc Direct TLR2 signaling is critical for NK cell activation and function in response to vaccinia viral infection
    Jennifer Martinez
    Department of Immunology, Duke University Medical Center, Durham, North Carolina, United States of America
    PLoS Pathog 6:e1000811. 2010
    ....
  8. pmc The TLR9-MyD88 pathway is critical for adaptive immune responses to adeno-associated virus gene therapy vectors in mice
    Jiangao Zhu
    Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA
    J Clin Invest 119:2388-98. 2009
    ....
  9. pmc Induction of type I IFN is required for overcoming tumor-specific T-cell tolerance after stem cell transplantation
    Ian Horkheimer
    Departments of Medicine, Duke University Medical Center, Durham, NC 2771, USA
    Blood 113:5330-9. 2009
    ..Collectively, these results may suggest effective immunotherapeutic strategies for treating cancer after stem cell transplantation...
  10. pmc Innate immune recognition of viruses and viral vectors
    Xiaopei Huang
    Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
    Hum Gene Ther 20:293-301. 2009
    ..In this review we first discuss our current understanding of innate immune recognition of viruses in general, and then focus on the innate immune responses to viral vectors for gene therapy...
  11. pmc A critical role for direct TLR2-MyD88 signaling in CD8 T-cell clonal expansion and memory formation following vaccinia viral infection
    Michael Quigley
    Department of Medicine, Duke University Medical Center, Durham, NC, USA
    Blood 113:2256-64. 2009
    ..These results identify a critical role for intrinsic TLR2-MyD88 signaling and PI3K-Akt pathway activation in CD8 T-cell clonal expansion and memory formation in vivo and could lead to the development of new vaccine approaches...
  12. ncbi A critical role for type I IFN-dependent NK cell activation in innate immune elimination of adenoviral vectors in vivo
    Jiangao Zhu
    Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA
    Mol Ther 16:1300-7. 2008
    ....
  13. ncbi STAT1 signaling in CD8 T cells is required for their clonal expansion and memory formation following viral infection in vivo
    Michael Quigley
    Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
    J Immunol 180:2158-64. 2008
    ..These results identify a critical role for type I IFN-STAT1 signaling in multiple stages of CD8 T cell response in vivo and suggest that strategies to activate type I IFN-STAT1 signaling pathway may enhance vaccine potency...
  14. ncbi Direct action of type I IFN on NK cells is required for their activation in response to vaccinia viral infection in vivo
    Jennifer Martinez
    Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
    J Immunol 180:1592-7. 2008
    ..Our findings may help design effective strategies for the control of poxviral infections in vivo...
  15. ncbi CD4 T cells are required for CD8 T cell survival during both primary and memory recall responses
    Patricia Novy
    Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
    J Immunol 179:8243-51. 2007
    ..Our study indicates that CD4 T cells play a crucial role in multiple stages of CD8 T cell response to vaccinia virus infection and may help to design effective vaccine strategies...
  16. ncbi Extent of stimulation controls the formation of memory CD8 T cells
    Michael Quigley
    Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC 27710, USA
    J Immunol 179:5768-77. 2007
    ..Collectively, our data suggest that the extent of stimulation controls CD8 memory formation via activation of Akt and may provide important insights into the design of effective vaccines...
  17. ncbi Type I IFN signaling on both B and CD4 T cells is required for protective antibody response to adenovirus
    Jiangao Zhu
    Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC 27710, USA
    J Immunol 178:3505-10. 2007
    ..The results may suggest potential strategies for improving adenovirus-mediated gene therapy in vivo and/or the design of effective vaccines for cancer and infectious diseases...
  18. pmc Innate immune response to adenoviral vectors is mediated by both Toll-like receptor-dependent and -independent pathways
    Jiangao Zhu
    Department of Medicine, Duke University Medical Center, Box 3502, Durham, NC 27710, USA
    J Virol 81:3170-80. 2007
    ..Our results that suggest strategies to interfere with type I IFN pathway may improve the outcome of adenovirus-mediated gene therapy, whereas approaches to activate the type I IFN pathway may enhance vaccine potency...
  19. pmc Innate immunity against vaccinia virus is mediated by TLR2 and requires TLR-independent production of IFN-beta
    Jiangao Zhu
    Department of Medicine, Duke University Medical Center, Box 3502, Durham, NC 27710, USA
    Blood 109:619-25. 2007
    ....