Oral carcinoma (OC) represents a significant health problem in the U.S. Standard therapies, including surgery, radiation therapy, and chemotherapy have not significantly changed the outcome of OC during the last decades. To improve therapy of OC, it is necessary to understand the biology governing selection, death and survival of OC cells. Although immune surveillance is expected to protect against cancer, cancer development occurs in apparently immunocompetent hosts. Our recent studies have demonstrated that immune effector cells, such as natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), express a variety of the TNF family ligands, while cancer cells express the corresponding receptors. These complementary pairs of receptor-ligands interact and mediate apoptosis in cancer cells. We have discovered that this killing cannot be induced by the engagement of a single ligand-receptor pair. It is only inducible by simultaneous interactions of at least three different ligand-receptor. The apoptotic pathway can be completely inhibited by interference with the engagement of a single ligand-receptor pair. OC cells, like other cancer cells, express a variety ro the TNF family receptors and yet are relatively resistant to apoptosis mediated by their ligation. This apoptotic pathway can be completely inhibited by interference with the engagement of a single ligand-receptor pair. OC cells, like other cancer cells, express a variety of the TNF family receptors and yet are relatively resistant to apoptosis mediated by their ligation. Furthermore, peripheral blood cells of OC patients show impaired ability to induced apoptosis in OC targets. Based on these novel observations, we hypothesize that OC cells are resistant to control by the immune system, in par, because they have been selected in vivo via the TNF family ligands for the defective TNF family receptors. Also, we postulate that there may be similar defects in the TNF family ligands on immune effector cells in OC patients.. Either of these abnormalities could interfere with effective host defense against transformed cells and thereby facilitate or enable the development of OC. To test these hypotheses, we propose to show that apoptosis of OC cells is a universal mechanism which can be induced by a variety of immune cells through simultaneous engagement of at least three TNF family ligands (Aim 1). Possible abnormalities of the TNF family receptors on OC cells as well as ligands on immune cells will be investigated by assessing levels of their cell membrane expression, secretion of soluble forms, and the ability to signal or mediate apoptosis, respectively (Aims 2 and 3). Also, various immune interventions will be tested in vitro in order to correct abnormalities of the TNF family receptors on OC cells and/or their ligands on immune cells of OC patients and thereby render OC cells susceptible to apoptosis (Aim 4). This study will determine the role of the TNF family receptors and ligands in escape of OC from immune control and might lead to the development of novel strategies for determining prognosis or improving therapy of OC.