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IL-4-Transfected Tumor Cell Vaccines Activate Tumor-Infiltrating Dendritic Cells and Promote Type-1 Immunity¹

Junichi Eguchi^2,*, Naruo Kuwashima^2,*, Manabu Hatano^*, Fumihiko Nishimura^*, Jill E. Dusak^*, Walter J. Storkus and Hideho Okada^3,*,,

Departments of^* Neurological Surgery, Dermatology, and Surgery, University of Pittsburgh School of Medicine, and Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213

We previously demonstrated that IL-4 gene-transfected glioma cell vaccines induce effective therapeutic immunity in preclinical glioma models, and have initiated phase I trials of these vaccines in patients with malignant gliomas. To gain additional mechanistic insight into the efficacy of this approach, we have treated mice bearing the MCA205 (H-2^b) or CMS-4 (H-2^d) sarcomas. IL-12/23 p40^–/– and IFN-^–/– mice, which were able to reject the initial inoculation of IL-4 expressing tumors, failed to mount a sustained systemic response against parental (nontransfected) tumor cells. Paracrine production of IL-4 in vaccine sites promoted the accumulation and maturation of IL-12p70-secreting tumor-infiltrating dendritic cells (TIDCs). Adoptive transfer of TIDCs isolated from vaccinated wild-type, but not IL-12/23 p40^–/–, mice were capable of promoting tumor-specific CTL responses in syngeneic recipient animals. Interestingly, both STAT4^–/– and STAT6^–/– mice failed to reject IL-4-transfected tumors in concert with the reduced capacity of TIDCs to produce IL-12p70 and to promote specific antitumor CTL reactivity. These results suggest that vaccines consisting of tumor cells engineered to produce the type 2 cytokine, IL-4, critically depend on type 1 immunity for their observed therapeutic efficacy.

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