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Expression of a Soluble TGF-β Receptor by Tumor Cells Enhances Dendritic Cell/Tumor Fusion Vaccine Efficacy¹

Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109

Dendritic cell (DC)-based antitumor immunotherapy is a promising cancer therapy. We have previously shown that tumor-derived TGF-β limits the efficacy of the DC/tumor fusion vaccine in mice. In the current study we investigated the effect of neutralizing tumor-derived TGF-β on the efficacy of the DC/tumor fusion vaccine. An adenovirus encoding human TGF-β receptor type II fused to the Fc region of human IgM (Adv-TGF-β-R) or a control adenovirus encoding LacZ (Adv-LacZ) was used to express a soluble form of the neutralizing TGF-β receptor (TGF-β-R). Murine breast carcinoma cells, 4T1, but not bone marrow-derived DCs, were successfully transfected with Adv-TGF-β-R (4T1+Adv-TGF-β-R) using a multiplicity of infection of 300. Immunization with irradiated 4T1+Adv-TGF-β-R tumor cells conferred enhanced antitumor immunity compared with immunization with irradiated 4T1+Adv-LacZ tumor cells. The DC/4T1+Adv-TGF-β-R fusion vaccine offered enhanced protective and therapeutic efficacy compared with the DC/4T1-Adv-LacZ fusion vaccine. Because TGF-β is known to induce regulatory T cells (Tregs), we further showed that the DC/4T1+Adv-TGF-β-R fusion vaccine induced fewer CD4⁺CD25⁺Foxp3⁺ Tregs than the DC/4T1+Adv-LacZ fusion vaccine in vitro and in vivo. The suppressive role of splenic CD4⁺CD25⁺ Tregs isolated from mice immunized with DC/4T1+Adv-LacZ was demonstrated using a CTL killing assay. Similar enhanced therapeutic efficacy was observed in murine renal cell carcinoma, RenCa, which expresses a high level of TGF-β. We conclude that the blockade of tumor-derived TGF-β reduces Treg induction by the DC/tumor fusion vaccine and enhances antitumor immunity. This may be an effective strategy to enhance human DC-based antitumor vaccines.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from Department of Defense (to J.-J.C.) and by the Foundation for Digestive Health and Nutrition (to J.Y.K.).

² Address correspondence and reprint requests to Dr. John Y. Kao, Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, 6520A Medical Sciences Research Building I, Special Postal Code 5682, 1150 West Medical Center Drive, Ann Arbor, MI 48109. E-mail address: jykao{at}umich.edu

³ Abbreviations used in this paper: DC, dendritic cell; Treg, regulatory T cell; TGF-β-R, TGF-β receptor; MOI, multiplicity of infection; CM, complete medium; RenCa, murine renal cell carcinoma.