REGULATION OF MACROPHAGE ACTIVITY: IN VITRO VS IN VIVO

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Differences in biologic responses of human monocytes and macrophages are well recognized, although little is known about the regulation of activation and mechanisms of their antitumor activity. Granulocyte-macrophage colony stimulating factor (GM-CSF) is currently being evaluated in a clinical trial in patients with cancer at our institution. Previous work has demonstrated that GM-CSF induces distinctive responses in monocytes and alveolar macrophages. GM-CSF activates cell-associated tumoricidal activity in alveolar macrophages from both normal volunteers and patients with cancer. In contrast, GM-CSF has little effect on cell-associated antitumor activity of blood monocytes, although other properties associated with antitumor activity (e.g. superoxide anion production. secretion of tumor necrosis factor, interleukin-6, interferon) are upregulated in monocytes after exposure to GM-CSF. Based upon these data, maturation is hypothesized to be a critical determinant of GM-CSF induced macrophage tumoricidal response. The first specific aim will determine if divergent cellular mechanisms are involved in the contrasting GM-CSF responses of monocytes and alveolar macrophages. In vitro cytokine gene expression and production (interleukin-1, tumor necrosis factor, interleukin-6, interferon) will be assessed for correlation with cell-associated tumoricidal activity. We will also determine whether GM-CSF-induced cytokines sequentially or concurrently with GM-CSF further modulate macrophage/monocyte gene expression and functional activity. In addition, the response to GM-CSF of intratumor macrophages from resected tissue specimens will be determined. The second specific aim will be to link this project with the clinical trial by evaluating the effect of in vivo exposure to GM-CSF on the specific cellular and/or molecular processes shown in specific aim 1 to be associated with the GM-CSF responses of monocytes/macrophages. In addition, studies will be carried out with tumor biopsy specimens obtained prior to and during GM-CSF therapy to determine whether GM-CSF-induced changes are detectable in vivo at the tumor site. This investigation will provide data on both the regulation of tumoricidal responses and mechanisms of antitumor activity in human monocytes and macrophages. Ultimately such findings will provide a basis for the future design of more effective immunological approaches to cancer therapy.