The purpose of this research is to understand the interactions that occur between malignant cells and cells of the host immune system and to determine how radiation may alter these interactions. In this proposal cytokine production by the host cells and growth factor production by the tumor cells will be studied as a mechanism by which the immune responses to tumors are regulated. Mechanisms by which treatment modalities such as radiation and the tumor microenvironment alter the production and activity of these soluble factors will also be explored. Growth of tumors, even those with a demonstrable immunogenicity can often proceed progressively. Several mechanisms may be operative in allowing this to occur, but one that appears to be prevalent is the release by tumor cells of factors that inhibit immunoproliferative responses. The EMT6 tumor, a spontaneous BALB/c mammary carcinoma, will be used as a model of immunosuppressive tumors. Research from this laboratory has shown that EMT6 tumors growing in syngeneic hosts contain cytolytic T lymphocytes capable of lysing EMT6 cells. Despite the presence of cytolytic cells, the tumors grow unchecked. Recent results have shown that the EMT6 tumor produces soluble factors that inhibit the proliferation of lymphocytes. This inhibitory activity is largely due to the production of transforming growth factor-beta (TGF-beta) by EMT6. Cytokines produced by host immune cells play a major role in the communication among cells of the immune system and in regulating immune responses, Macrophages, which are a predominant host cell population within EMT6 and many tumors, produce a large number of different cytokines, including IL-1, IL-6, TNF-alpha, and IFN-gamma, all of which may have marked effects on T cells and on tumor cells themselves. In turn, the T cells also produce several different lymphokines depending on whether they are T helper or T cytotoxic cells. Although the interactions among these different cytokines may be complex, the availability of recombinant molecules and specific monoclonal antibodies make it possible to study their respective roles in a systematic fashion. The multicellular spheroid model and the specific cytolytic T cells reactive with the EMT6 tumor will allow us to determine the role of these cytokines in regulating the interactions between host and tumor cells. This information is vital to design efficacious immunotherapy strategies to combat neoplastic disease.