Although interleukin (IL)-4 is often regarded as a Type-2 response inducer, recent studies have demonstrated that local IL-4 delivery at the site of vaccination activates local antigen-presenting cells (APC) and promote Type-1 T cell responses. We have demonstrated IL-4 gene transfected glioma cell vaccines induce effective therapeutic immunity in preclinical glioma models, and initiated phase I trials in patients with malignant gliomas. To determine the critical mediators of the IL-4-transfected tumor vaccines, we employed MCA205 and CMS-4 sarcoma models and syngeneic animals. Although wild type, IL-12/23p40-/- and interferon(IFN)-γ-/- mice rejected initial inoculation of IL-4 transfected tumors, IL-12/23p40-/- and IFN-γ-/- mice as well as athymic mice failed to mount a sustained systemic response against rechallenge with parental tumor cells. Ectopic IL-4 expression at the vaccine site enhanced the number of tumor infiltrating dendritic cells (TIDC) and their expression of IL-12p70. Adoptive transfer of wild type-TIDCs obtained from IL-4 expressing tumor, but not IL-12/23p40-/--TIDC, elicited a tumor specific CTL response in the recipient animals, suggesting that IL-12/23 expression by TIDCs play a critical role in IL-4 transfected tumor vaccines. To further delineate the roles of Type-1 and -2 cytokine responses in the IL-4 gene therapy, we employed STAT4-/- and STAT6-/- mice. Interestingly, both STAT4-/- and STAT6-/- mice failed to suppress the growth of IL-4 expressing syngeneic tumors. TIDCs from STAT6-/- mice failed to enhance the expression of IL-12p70, and cell surface expression of MHC Class II and CD86 were lower than the wild-type mice-derived TIDCs, suggesting that STAT6 plays a critical role in the maturation of TIDC. Nevertheless, splenocytes from STAT6-/- mice immunized with IL-4 transfected tumors, but not STAT4-/- mice, mounted a tumor specific CTL response against parental tumor cells even though its level was lower than that in the wild-type mice. Furthermore, splenocytes from STAT4-/- mice immunized with IL-4 transfected tumors failed to produce IFN-γ. These results demonstrate critical roles of host-Type-1 cytokine responses in IL-4 transfected tumor vaccines. As cancer patients often display impaired Type-1 cytokine response, it may be of importance to correlate host-Type-1 cytokine status and the response to IL-4 gene transfected tumor cell vaccines.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]