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.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Transplantation, Tolerance, and Tumor Immunology (TTT)
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Venkatachalam, Sundaresan
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University of Pittsburgh
Schools of Medicine
United States
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Ge, Lisheng; Vujanovic, Nikola L (2017) Soluble TNF Regulates TACE via AP-2? Transcription Factor in Mouse Dendritic Cells. J Immunol 198:417-427
Sobo-Vujanovic, Andrea; Vujanovic, Lazar; DeLeo, Albert B et al. (2016) Inhibition of Soluble Tumor Necrosis Factor Prevents Chemically Induced Carcinogenesis in Mice. Cancer Immunol Res 4:441-51
Sobo-Vujanovic, Andrea; Munich, Stephan; Vujanovic, Nikola L (2014) Dendritic-cell exosomes cross-present Toll-like receptor-ligands and activate bystander dendritic cells. Cell Immunol 289:119-27
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