The long-term objective of this application is to determine whether the initiation and progression of oral carcinomas in vivo is due to the induction of functional inactivation and cell death of Natural Killer cells. Human carcinomas of the head and neck and the oral cavity induce the least detectable cell-mediated anti-tumor immune responses, and decreased frequencies of proliferating lymphocytes have been observed in the peripheral blood and tumor tissue of oral cancer patients. More importantly, regressing oral tumors contain significantly larger numbers of functional NK cells when compared to those associated with primary tumors. Thus, the central hypothesis is that the initiation of NK cell apoptotic signaling by factors secreted from the NK cells or elaborated by oral cancer cells during their interaction will result in the inactivation of NK cell cytotoxic function, thereby enhancing the survival of oral carcinoma cells. To delineate the mechanisms by which Natural Killer cells lose their cytotoxic function and undergo apoptotic cell death in the presence of oral cancer cells, the following will be examined: 1. The role of oral tumor cell induced TNF-alpha release from NK cells in the absence of IFN-gamma secretion in inactivation and cell death of NK cells. There are also plans to study the effect of oral tumor cells on inhibition of TNF receptor associated protein (TRAFs) and NFkappaB functions in NK cells. 2. The effect of oral tumor cell elaborated TGF-beta on the inhibition of NFkappaB activity in NK cells, and subsequent induction of NK cell inactivation and cell death. 3. The roles of oral tumor cell induced stress related c-jun N-terminal kinase (JNK) and protein tyrosine phosphatase 1C (PTP1C) signaling in NK cells and in the regulation of TNF-alpha and NFkappaB and induction of NK cell inactivation and cell death by oral carcinoma cells. 4. The differential effects of sensitive and resistant oral carcinoma cells on NK cell inactivation and cell death. 5. The effect of patient derived oral tumor cells in NK cell inactivation and cell death. Using both in vitro established oral tumor lines and in vivo studies utilizing tumor tissues and immune cells from individuals with cancer of the oral cavity, the exact mechanisms by which oral carcinoma cells exert an immunosuppressive effect on NK cells will be examined. Understanding the mechanisms by which NK cells become functionally inactivated and undergo cell death will enable design strategies to reverse such inactivation and ensure effective immunity against oral tumor cells.
