Abstract

B7-H1 and B7-H4 are two B7 family molecules with potent immunosuppressive functions. Upon interaction with their respective counter-receptors on T cells, these B7Hs constitute essential immunologic checkpoints in tuning down T cell responses to prevent overly activated and harmful immune responses during infection and inflammation. The long-term goal of this study is to elucidate the mechanisms of B7-H1 and B7-H4 in the induction of tolerance in tumor microenvironment as a means to design novel approaches to enhance cancer immunity. Recent studies demonstrate that B7-H1 is broadly up-regulated on cancer cells, tumor-infiltrating lymphocytes and other stromal cells. In addition, expression of B7-H1 is found to correlate with poor prognosis of renal cell carcinoma and esophageal cancer. Inhibitory effect of B7-H1 on T cells is at least partially mediated through binding to receptor PD-1. B7-H4 is also upregulated in various types of cancer cells. In addition, B7-H4 is found to express on tumor-infiltrating macrophages in high level and renders their suppressive function. The central hypothesis of this proposal is that B7-H1 and B7-H4 in tumor microenvironment induces tolerance so as to prevent immune destruction. Using mice with spontaneous prostate cancer as a model, we will use B7-H1/B7-H4 specific neutralizing monoclonal antibodies as a general approach to determine the role of these molecules in T cell tolerance and cancer progression. In addition, B7-H1/B7-H4 deficient mice will be employed to selectively ablate the expression of these molecules in subsets of host and immune cells to dissect the mechanisms of cancer microenvironment B7- H1 and B7-H4 in the induction of immune tolerance. The contribution of PD-1 on T cells and stromal cells in cancer microenvironment will also be evaluated. By the completion of these studies, we will gain insight into tolerance mechanisms of B7-Hs in cancer microenvironment and, more importantly, provide the basis for future design of immunotherapy. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA097085-06
Application #
7266160
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Howcroft, Thomas K
Project Start
2002-07-01
Project End
2012-05-31
Budget Start
2007-08-01
Budget End
2008-05-31
Support Year
6
Fiscal Year
2007
Total Cost
$363,450
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Dermatology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Zhu, Yuwen; Yao, Sheng; Augustine, Mathew M et al. (2016) Neuron-specific SALM5 limits inflammation in the CNS via its interaction with HVEM. Sci Adv 2:e1500637
Flies, Dallas B; Higuchi, Tomoe; Chen, Lieping (2015) Mechanistic Assessment of PD-1H Coinhibitory Receptor-Induced T Cell Tolerance to Allogeneic Antigens. J Immunol 194:5294-304
Yao, Sheng; Zhu, Yuwen; Chen, Lieping (2013) Advances in targeting cell surface signalling molecules for immune modulation. Nat Rev Drug Discov 12:130-46
Chen, Lieping; Flies, Dallas B (2013) Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol 13:227-42
Yao, Sheng; Chen, Lieping (2013) Adaptive resistance: a tumor strategy to evade immune attack. Eur J Immunol 43:576-9
Zhu, Yuwen; Yao, Sheng; Iliopoulou, Bettina P et al. (2013) B7-H5 costimulates human T cells via CD28H. Nat Commun 4:2043
Taube, Janis M; Anders, Robert A; Young, Geoffrey D et al. (2012) Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med 4:127ra37
Yao, Sheng; Zhu, Yuwen; Zhu, Gefeng et al. (2011) B7-h2 is a costimulatory ligand for CD28 in human. Immunity 34:729-40
Flies, Dallas B; Wang, Shengdian; Xu, Haiying et al. (2011) Cutting edge: A monoclonal antibody specific for the programmed death-1 homolog prevents graft-versus-host disease in mouse models. J Immunol 187:1537-41
Zhu, Yuwen; Yao, Sheng; Chen, Lieping (2011) Cell surface signaling molecules in the control of immune responses: a tide model. Immunity 34:466-78

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