INTERFERON GAMMA SIGNALING DEFECTS IN TUMOR EVASION

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Recently, we made the novel observation that endogenously produced IFNgamma exerts direct effects on tumor cells in mice that result in enhanced recognition and elimination of the tumor by the immune system. This data implies that IFNgamma forms the basis of a tumor surveillance system in immunocompetent hosts. We have also found that certain types of tumors become IFNgamma unresponsive and may thereby escape immune recognition. The overall focus of this grant application is to define IFNgamma's effects on tumors that result in enhanced immune recognition/elimination and to elucidate the genetic and acquired mechanisms used by tumors to circumvent the process. To achieve this goal we intend to pursue the following four specific aims. Specific Aim 1: Define the participation of IFNgamma in mediating tumor surveillance in mice. We will better define the process of IFNgamma dependent tumor surveillance and assess the relative importance of IFNgamma's effect on nascently forming transformed cells and host immune cells. Specific Aim 2: Define the defect(s) in IFNgamma insensitive tumors that render them resistant to immune elimination. We will determine whether IFNgamma insensitivity at the level of the tumor influences antigen processing and/or presentation, co-stimulation, T cell-target cell contact and/or sensitivity of the tumor to T cell killing processes. Specific Aim 3: Assess the role of IFNgamma receptor beta chain mechanism underlying our recent observation that IFNgamma desensitizes tumor cells and macrophages to subsequent IFNgamma treatment giving particular emphasis to the likely possibility that this process is the result of ligand induced in tumor cells is a common or rare event during tumorigenesis and define the molecular basis of IFNgamma unresponsiveness in human and murine tumors. We will (a) determine whether tumors formed in IFNgamma sensitive mice or human cancer patients develop genetic or adaptive insensitivity to IFNgamma and (b) characterize the molecular basis of the IFNgamma signaling defects found in four IFNgamma insensitive human lung adenocarcinoma cell lines that we have already identified. Taken together these studies should provide us with important insights into the role of IFNgamma in promoting immune responses to tumors and into the strategies used by tumors to escape IFNgamma's actions. Understanding the latter process will be particularly important in the development of new IFNgamma based therapeutic or diagnostic strategies to be used in treatment of cancer.