The role of interleukin-10 in immune escape by a murine transitional cell carcinoma

Interleukin (IL)-10 is a potent immunosuppressive cytokine that is found in elevated quantities both at the tumor site and systemically in a variety of cancers. Given the potent suppressive properties of this cytokine, we hypothesized that its presence at the site of progressively growing tumors represents an immune escape mechanism utilized by tumors to avoid detection by the immune system. The thesis that follows examines issues related to this hypothesis. ^ We describe two features of a murine model of transitional cell carcinoma, MB49, that render it an attractive in vivo model with which to study the effect of IL-10 on tumor immunity. First, MB49 expresses the male antigen, H-Y. Thus, when grown in syngeneic female mice, H-Y provides a surrogate tumor-specific antigen for study. Second, MB49 does not produce IL-10 itself but rather induces infiltrating cells to produce IL-10. Consequently, growth of MB49 in IL-10 knockout (KO) mice, whose infiltrating cells are unable to produce IL-10, allows for the removal of the IL-10 normally associated with this tumor. Using MB49, we demonstrate that tumor-induced IL-10 inhibits the generation of a type I immune response against a tumor antigen as measured by Interferon (IFN)-γ production, cytotoxic T lymphocyte (CTL) generation, and delayed type hypersensitivity (DTH) reaction. Furthermore when tumor-induced IL-10 is removed, type 1 immunity is restored and tumors are completely rejected in up to 40 percent of animals. ^ Interestingly, during the course of these studies conflicting reports emerged in the literature regarding the effect of IL-10 in tumor systems. Those studying tumors engineered to produce IL-10 by way of gene-transfection uniformly reported that IL-10 enhances the anti-tumor immune response. In contrast, those studying IL-10 in tumor systems by other means consistently reported that IL-10 inhibits anti-tumor immunity. This led us to speculate that the method of study (i.e., gene-transfection vs. non gene-transfection) was the reason for the discrepancy. We addressed this hypothesis directly by transfecting MB49 with IL-10. We show that the disparate effects of IL-10 on tumor immunity are indeed due to the different modes of IL-10 production in the various studies. ^ In summary, our studies clearly demonstrate that IL-10 inhibits anti-tumor immunity. Furthermore, we provide a possible explanation for the discrepancy that exists concerning the role of this cytokine in tumor systems. These findings have important implications relative to the development of immunotherapy for the treatment of cancer.