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 microenvironment conditions within solid tumors and therapies such as radiation may alter these interactions. Generation of effective anti-tumor immunity requires that immune cells, such as specific cytolytic T lymphocytes (CTL), receive adequate antigenic stimulation, migrate and extravasate into the tumor site, and once there be able to function under the conditions present within the tumor. These conditions, particularly they hypoxia found within tumors are of considerable interest, because hypoxia can hava dose modifying effect on therapy modalities, particularly radiotherapy, but probably also chemotherapy and perhaps immunotherapy. Experimental and clinical studies on the role o hypoxia in limiting treatment efficacy have been limited by the lack of a reliable technique to identify and quantify hypoxic cells at the level of resolution needed. Our recent development of monoclonal antibodies against a new nitroimidazole compound, 2-(2-nitro-1H-imidazol-1yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide or EF5, that selectively binds gypoxic cells now allows an acurate assessment of the extend of hypoxia within tumors at the single cell level. In this proposal, we will determine how cytokines produced by both malignant and host cells within the local microenvironment of tumors affect 1) the function of immune cells and 2) the microenvironment within the tumors. We hypothesize that hypoxic conditions within solid tumors may limit the infiltration and function of immunologically active host cells and that cytokines can alter the level of hypoxia. We will explore how hypoxic conditions within tumors affect expression of adhesion molecules on vascular endothelial cells and on the tumor cells themselves. The effects of radiotherapy on both cytokine production within tumors and on adhesion molecule expression will also be studied to provide information essential for the optimal treatment of malignant disease.
Showing the most recent 10 out of 66 publications
