The unique ability of dendritic cells to potently stimulate naive T lymphocytes has made them prime candidates for cancer immunotherapy. In several rodent models, vaccination with antigen-pulsed dendritic cells confers protection against subsequent tumors. The inability of DC-based vaccines to cause significant regression of existing tumors has been attributed, in part, to the negative immunomodulatory effects of the tumor microenvironment. A number of tumor-derived products have been suggested to promote tumor establishment and progression by interfering with DC functions required for the induction of a potent antitumor response. One of the best characterized of these tumor-derived factors is Transforming Growth Factor-beta (TGF-beta), a multifunctional cytokine that exerts potent suppressive effects on cells of the immune system. In tumor biopsies from melanoma, breast and lung cancer patients, TGF-beta immunostaining has been directly correlated with metastasis, disease recurrence and mortality. TGF-beta specifically interferes with DC maturation, chemotaxis, antigen recognition and T cell activation. These findings strongly suggest that strategies that increase the resistance of DCs to TGF-beta-mediated immunosuppression should enhance the effectiveness of DC-based vaccines. The hypothesis to be tested is that blockade of TGF-beta-mediated signaling in DCs will abrogate tumor-derived, TGF-beta-mediated immunosuppression leading to ore effective DC vaccines.
The Specific Aims of this study are to: 1) determine the effect of tumor-derived TGF-beta on in vivo migratory and immune stimulatory activities of DC 2) evaluate the impact of tumor-derived TGF-beta on DC vaccines. 3) block TGF-beta-mediated signal transduction in DCs in order to enhance the effectiveness of DC vaccines. 4) develop complementary approaches to improve the effectiveness of TGF-beta-resistant DC against established tumor. TGF-beta-mediated signal transduction will be abrogated by transfer of genes encoding a defective TGF-beta type II receptor or the TGF-beta inhibitory protein, Smad7 into DCs. These studies are expected to improve our understanding of the role of tumor-derived TGF-beta on DC function and lead to the development of improved methods for treating TFG-beta producing cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA094111-03
Application #
6706204
Study Section
Special Emphasis Panel (ZRG1-ET-1 (02))
Program Officer
Hecht, Toby T
Project Start
2002-01-11
Project End
2005-12-31
Budget Start
2004-01-01
Budget End
2004-12-31
Support Year
3
Fiscal Year
2004
Total Cost
$244,673
Indirect Cost
Name
University of Arizona
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Morigasaki, Susumu; Ikner, Aminah; Tatebe, Hisashi et al. (2013) Response regulator-mediated MAPKKK heteromer promotes stress signaling to the Spc1 MAPK in fission yeast. Mol Biol Cell 24:1083-92
Garrison, Kendra; Hahn, Tobias; Lee, Wen-Cherng et al. (2012) The small molecule TGF-? signaling inhibitor SM16 synergizes with agonistic OX40 antibody to suppress established mammary tumors and reduce spontaneous metastasis. Cancer Immunol Immunother 61:511-21
Rausch, Matthew P; Hahn, Tobias; Ramanathapuram, Lalitha et al. (2009) An orally active small molecule TGF-beta receptor I antagonist inhibits the growth of metastatic murine breast cancer. Anticancer Res 29:2099-109
Hahn, Tobias; Alvarez, Irene; Kobie, James J et al. (2006) Short-term dietary administration of celecoxib enhances the efficacy of tumor lysate-pulsed dendritic cell vaccines in treating murine breast cancer. Int J Cancer 118:2220-31
Hahn, Tobias; Szabo, Lajos; Gold, Mikhal et al. (2006) Dietary administration of the proapoptotic vitamin E analogue alpha-tocopheryloxyacetic acid inhibits metastatic murine breast cancer. Cancer Res 66:9374-8
Ramanathapuram, Lalitha V; Hahn, Tobias; Graner, Michael W et al. (2006) Vesiculated alpha-tocopheryl succinate enhances the anti-tumor effect of dendritic cell vaccines. Cancer Immunol Immunother 55:166-77
Ramanathapuram, Lalitha V; Hahn, Tobias; Dial, Sharon M et al. (2005) Chemo-immunotherapy of breast cancer using vesiculated alpha-tocopheryl succinate in combination with dendritic cell vaccination. Nutr Cancer 53:177-93
Ramanathapuram, Lalitha V; Kobie, James J; Bearss, David et al. (2004) alpha-Tocopheryl succinate sensitizes established tumors to vaccination with nonmatured dendritic cells. Cancer Immunol Immunother 53:580-8
Robey, Ian F; Schluter, Samuel F; Akporiaye, Emmanuel et al. (2002) Human monoclonal natural autoantibodies against the T-cell receptor inhibit interleukin-2 production in murine T cells. Immunology 105:419-29