Lung cancer is the leading cause of cancer-related death in the united States. One major impediment to effective therapy is our inadequate understanding of how lung caner escapes immune surveillance and inhibits antitumor immunity. Interleukin 10 (IL- 10) is a potent immunosuppressive cytokine present in the local tumor environment in non--small cell lung cancer (NSCLC). In this proposal we evaluate the function and regulation of IL-10 in NSCLC in both a murine model in vivo and in human cells in vitro. In vitro, IL-10, murine lung tumors grow more rapidly and lead to decreased survival compared to controls. We hypothesize that IL- 10 inhibits specific tumor antigen-presentation and /or recognition in vivo. To test this hypothesis we will evaluate the capacity of IL- 10 transgenic mice to present specific tumor antigen and for IL-10 to inhibit the activation and function of human antigen-presenting cells in vitro. In addition to tumor cells, other cellular components of the tumor microenvironment may contribute to tumor-associated immunosuppression. NSCLC-derived prostaglandin E@ (PGE2) potently induces lymphocyte and macrophage IL-10 production. While the interaction between lung tumor cells and mononuclear leukocytes is complex, one focus of our in vitro studies will be to identify the mechanism(s) by which human NSCLC produce PGE2 and up-regulate leukocyte-derived IL-10. We hypothesize that activation of cyclooxygenase-2 (COX-2), the cytokine-inducible isoform of cyclooxygenase, is primarily responsible for high level PGE2 production by lung tumor cells.
The specific aims of this research are: 1) To determine the in vivo immunoregulatory role of IL-10 in a murine model of NSCLC, 2) To evaluate the relationship between COX-2 expression, IL-10 induction and antitumor responses in vivo, 3) To define the COX-2-dependent pathway regulating human NSCLC-derived PGE2 formation and 4) To evaluate the biologic consequences of IL-10 on the generation of specific anti-tumor immunity by human antigen-presenting cells. Tumor-derived prostaglandins may play an important role in augmenting lymphocyte production of inhibitory cytokines such as IL-10 that interfere with effective host cell-mediated anti-tumor immune responses. We anticipate that this study will add to our understanding of the complex interaction between pulmonary tumor- derived PGE2 and the cytokine network at the tumor site.
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