The presentation of tumor antigens and initiation of specific immune responses are the primary responsibility of professional antigen presenting cells. Dendritic cells (DC) are the most potent antigen presenting cells, and play a crucial role in the induction of primary immune responses. Recently, the applicant and others have demonstrated defective DC function in tumor bearing animals and in cancer patients. These defects were caused, at least in part, by tumor derived factors which dramatically inhibited the maturation of CD34+ hematopoietic stem cells into functional DC. One of the factors responsible for this defect was identified as tumor-derived vascular endothelial growth factor (VEGF). Preliminary data show that VEGF binding to the flt-1 receptor on hematopoietic stem cells may mediate reduced activity of the transcription factor NFkB, identifying the potential pathway responsible for this effect. The purpose of this application is to study tumor-associated defects in DC development in vitro and in vivo, and in particular to study the role of VEGF and its downstream signaling pathways in CD34+ stem cells. The ultimate goal of this project is to understand the role of these signals in DC differentiation and to develop immunotherapeutic strategies which counter this effect and enhance the effectiveness of immunotherapeutics in cancer patients. Specifically, in this project, the applicant will: 1) Characterize the nature of the cells derived from CD34+ cells in vitro after treatment with VEGF, and the possible role of other soluble factors in this process; 2) Assess the role of the VEGF receptor flt-1 in the inhibition of DC maturation in the presence of tumor-derived factors and that of the transcription factor NFkB in the defective functional maturation of dendritic cells in vitro; 3) Attempt to reproduce the inhibition of dendritic cell function in intact animals by prolonged infusion of recombinant VEGF alone or in combination with other factors; and 4) Test the efficacy of blockade of VEGF signaling on dendritic cell function, on the development of epitope-specific antitumor immunity, and on antitumor effects in syngeneic rodent tumor models.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA076321-02
Application #
2837775
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Hecht, Toby T
Project Start
1997-12-15
Project End
2002-11-30
Budget Start
1999-02-23
Budget End
1999-11-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Carbone, David P; Gandara, David R; Antonia, Scott J et al. (2015) Non-Small-Cell Lung Cancer: Role of the Immune System and Potential for Immunotherapy. J Thorac Oncol 10:974-84
Huang, Yuhui; Lin, Luping; Shanker, Anil et al. (2011) Resuscitating cancer immunosurveillance: selective stimulation of DLL1-Notch signaling in T cells rescues T-cell function and inhibits tumor growth. Cancer Res 71:6122-31
Novitskiy, Sergey V; Csiki, Ildiko; Huang, Yuhui et al. (2010) Anti-vascular endothelial growth factor treatment in combination with chemotherapy delays hematopoietic recovery due to decreased proliferation of bone marrow hematopoietic progenitor cells. J Thorac Oncol 5:1410-5
Novitskiy, Sergey V; Ryzhov, Sergey; Zaynagetdinov, Rinat et al. (2008) Adenosine receptors in regulation of dendritic cell differentiation and function. Blood 112:1822-31
Yang, Li; Huang, Jianhua; Ren, Xiubao et al. (2008) Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 13:23-35
Ryzhov, Sergey; Novitskiy, Sergey V; Zaynagetdinov, Rinat et al. (2008) Host A(2B) adenosine receptors promote carcinoma growth. Neoplasia 10:987-95
Huang, Yuhui; Chen, Xiaolan; Dikov, Mikhail M et al. (2007) Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis associated with elevated levels of VEGF. Blood 110:624-31
Csiki, Ildiko; Yanagisawa, Kiyoshi; Haruki, Nobuhiro et al. (2006) Thioredoxin-1 modulates transcription of cyclooxygenase-2 via hypoxia-inducible factor-1alpha in non-small cell lung cancer. Cancer Res 66:143-50
Dikov, Mikhail M; Ohm, Joyce E; Ray, Neelanjan et al. (2005) Differential roles of vascular endothelial growth factor receptors 1 and 2 in dendritic cell differentiation. J Immunol 174:215-22
Csiki, Ildiko; Morrow, Jason D; Sandler, Alan et al. (2005) Targeting cyclooxygenase-2 in recurrent non-small cell lung cancer: a phase II trial of celecoxib and docetaxel. Clin Cancer Res 11:6634-40

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