Mononuclear phagocytes are known to be an important system of host defense against tumor cells, bacteria, and other pathogens. A large body of evidence indicates that one important mediator of monocyte anti-tumor immune response is Tumor Necrosis Factor Alpha (TNF-alpha). Other studies indicate that local (i.e. in the microenvironment of the tumor cell) production of TNF-alpha by monocytes, rather than systemic levels, are more important to host defense and less toxic to the host. TNF-alpha represents one of several cytokines which are likely to act together in the immune response and modulate production of other cytokines at the site of tumors and inflammation. The interaction between tumor cells and monocytes at the membrane level, and the triggering of signal transduction pathways leading to TNF-alpha gene expression, are the subjects of this grant proposal. Over the last several years, our lab has purified and characterized a new 48 kd differentiation factor (DF) termed P48, initially isolated from tumor cell conditioned medium (CM). This DF was later found to induce peripheral blood monocytes to secrete TNF-alpha and IL-1 and to exist as an integral membrane form (termed mP48) on some tumor cell lines. Tumor cells are known to induce monocyte TNF-alpha production, and in this proposal we present evidence that mP48 is one tumor cell membrane molecule which mediates tumor cell-monocyte interaction leading to TNF-alpha secretion. We, therefore, propose to (1) identify and characterize the monocyte surface receptor which is stimulated by mP48 on tumor cells; (2) determine the-mechanism by which mP48 induces monocyte TNF-alpha secretion; and (3) determine the biochemical linkage of P48 polypeptide to membrane lipid in order to begin to determine the relationship between mP48 and P48 found in CM. A detailed understanding of tumor cell-monocyte interaction leading to TNF-alpha production will likely advance our understanding of tumor immunology and may lead to improved methods of non-systemic cytokine immunotherapy of cancer.
