Effector cell types participating in immune or innate responses to cancer cells include macrophage, K, NK and T cells. There has been considerable study of the regulation of T and NK cells, and of lymphokine activation of macrophage nonspecific killing. However, endogenous factors stimulating antibody-dependent cellular cytotoxicity (ADCC) in macrophages and K cells has received much less attention. With the advent of monoclonal antibodies as possible therapeutic agents for cancer, a better understanding of the control of cells participating in ADCC is necessary. This proposal is based on our recent study of lymphokine and other cytokine factors which stimulate in vitro human and murine macrophage ADCC to tumor targets.
The first aim i s to identify these human and murine factors in relation to interferon and MAF factor activating macrophages for nonspecific cytotoxicity. The relation to factors stimulating K-cell ADCC will also be determined.
The second aim i s to determine optimal conditions for stimulation of ADCC capacity in vivo, locally and systemically. Mice will be injected with purified murine factor and peritoneal and spleen ADCC capacity determined in the macrophage and nonadherent K-cell compartments. LPS will also be used in the mouse to induce factor production and stimulate ADCC.
The third aim i s to use purified factor in mice in combination with monoclonal antibody to test the therapeutic effectiveness of ADCC therapy. Transplantable leukemias in mice which can be arrested by systemic application of antibody after tumor inoculation will be used. The efficacy of factor therapy will be determined by the additional protective effect it confers, locally or systemically, when the tumor load is increased or antibody decreased or delayed. The overall goal is to determine methods for increasing the effectiveness of antibody therapy for cancer through stimulation of host ADCC capacity.
