Objectives of this study are to define the essential molecular mechanism of interaction between natural killer cells (NK) and dendritic cells (DC), the role of this mechanism in antitumor immune functions and, based on these insights, to develop efficient therapeutic strategies for treatment of cancer. NK and DC rapidly interact and reciprocally stimulate NK activation, DC maturation and polarized secretion of Th1-type cytokines. The early cellular cross-talk occurs in cell-to-cell contact, and is believed to be a critical regulatory mechanism of the quality and magnitude of innate and adaptive antitumor immune functions. Our preliminary studies provide novel compelling evidence that the cellular cross-talk leading to increased secretion of IFN-g by NK is mainly a non-secretory mechanism which is mediated via the interaction of DC transmembrane TNF (tmTNF) and NK TNF receptor 2 (TNFR2);and that the cellular interaction induces suppression of growth of established tumors. They also provide the indications that, in addition to TNF, CD40L and other members of tmTNF family ligands (tmTNFfL) might be significant mediators of NK-DC cross-talk. We hypothesized that NK and DC interact via multiple tmTNFfL and TNF family receptors (TNFfR) and reciprocally stimulate innate and adaptive antitumor immune mechanisms, and mediate control of tumor growth. This novel mechanism of NK-DC cross-talk might be impaired in cancer host, allowing tumor development and progression, and should be repaired and enhanced to efficiently treat cancer. This hypothesis will be tested in the following specific aims:
AIM 1. Demonstrate that NK-DC cross-talk is mediated by TNF and CD40L;
Aim 2. Determine the importance of NK-DC cross-talk via TNF and CD40L for development of antitumor immune mechanisms in vivo;
Aim 3. Develop efficient anticancer therapy based on enhanced NK-DC cross-talk by forced induction of increases in expression of TNF and CD40L.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE017150-04
Application #
7782761
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Venkatachalam, Sundaresan
Project Start
2007-04-09
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$349,688
Indirect Cost
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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