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 #
5R01CA097085-08
Application #
7623574
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
2009-06-01
Budget End
2010-05-31
Support Year
8
Fiscal Year
2009
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
Zhu, Yuwen; Yao, Sheng; Iliopoulou, Bettina P et al. (2013) B7-H5 costimulates human T cells via CD28H. Nat Commun 4:2043
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
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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