It is hypothesized that nonspecific cellular mediated cytotoxicity, as manifested in the natural killer (NK) and macrophage populations, is a major factor in the host response to solid carcinomas.
The specific aims of this proposal will be the delineation of the role of the host natural killer (NK) and cytotoxic macrophage repsonse in metastatic urogenital cancer. Briefly, the initial thrust of the project will be to assess the baseline stimulated and nonstimulated NK and cytotoxic macrophage activation in both the heterozygous (nu/+) and homozygous (nu/nu) athymic Balb c mice housed in the specific pathogen free (SPF) facility at the Atlanta VAMC. These mice, being athymic and therefore lacking mature T cells, are a good model in which to study non T lymphocyte tumor resistance. Cell surface phenotypes of effector cells will also be determined. Next, changes in the levels of both NK and cytotoxic macrophage levels will be measured following either intraperitoneal or subcutaneous transplantation of urogenital malignancies. Attempts will be made to correlate both changes in baseline as well as qualitative chages in responsiveness to nonspecific interferon inducers (Polyinosinic:polycytidilic acid (POIC), etc.) This portion will be a kinetic experiment following cytotoxic activity through the course of the development and spread of metastatic cancer. After determination of changes in the native host response, attempts to alter the spread of malignancy will be made through either 1) augmentation of the response by nonspecific interferon inducers such as POIC, 2) depletion of certain subsets by pretreatment with either antiserum or monoclonal antibodies directed towards certain specific cell surface phenotypes, or 3) passive transfer of activated cytotoxic cells. Concurrent assays of in vitro direct cytotoxic activity against he tumors will also be performed. Urogenital carcinomas comprised 27% of all malignancies in adult males as well as 15% of all cancer deaths in 1983. It is estimated that in these urologic malignancies, nearly 50% will be metastatic at the time of presentation. The goal of this research is to determine the role of the macrophage and NK cells in host immune response. Methods aimed at altering the host response may give clues to possible immunotherapeutic modalities in patients with metastatic cancer. Furthermore, the long term effects of the results of this study may prove to be of benefit to patients with malignancies originally at sites other than the genitourinary system.
