The research proposed in this renewal application is based on both the enhanced understanding of IFNgamma receptor signaling we have gained from studies previously supported by this grant and from our novel observation demonstrating that IFNgamma plays a critical role in promoting immune responses to primary and transplantable tumors and that the tumor itself is a critical target of IFNgamma's actions. Our recent work has revealed that a significant percentage of human and murine tumors develop an adaptive insensitivity to IFNgamma. Preliminary data reveals that this insensitivity may, at least in part, be due to inactivating mutations in the genes encoding the IFNgamma Receptor signaling proteins. We have thus formed the testable hypothesis that somatic mutations in genes encoding IFNgamma receptor signaling components may provide a developing tumor with a mechanism to escape immunologic detection and destruction. The overall goals of the proposed research are thus to define the mechanisms underlying development of IFNgamma insensitivity not only in established tumor cell lines but also in primary human and murine tumors, determine the functional outcome of this process and explore whether defining the IFNgamma sensitivity of primary human tumors at biopsy can serve as a prognostic indicator of a tumor patient's clinical course. This proposal thus represents a balanced combination of basic and translational research. To achieve our research goals we intend to pursue the following three specific aims. Specific Aim 1 seeks to elucidate the mechanisms leading to the development of IFNgamma insensitivity in human tumor cells lines and define the types of human tumor lines that display the insensitive phenotype. In Specific Aim 2 we will characterize the molecular mechanisms leading to IFNgamma-insensitivity in primary murine tumors and define the biological consequences of the insensitivity. In Specific Aim 3 we plan to determine whether IFNgamma insensitivity can be detected in fresh primary and metastatic human tumors and characterize the molecular mechanisms involved. These studies should thus define the molecular and genetic bases and clinical relevance of a frequent but previously unappreciated mechanism that tumors use to escape immunologic destruction that is of significant potential clinical relevance.