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* Department of Pathology,
Department of Surgery, and
Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China;
Department of Chemistry, University of Cambridge, United Kingdom; and
¶ Faculty of Medicine, Imperial College London, London, United Kingdom
The dendritic cell (DC)-based tumor immunotherapy has been a new promise of cure for cancer patients, but animal studies and clinical trials have thus far only shown limited success, especially in treating established tumors. Certain immunosuppressive mechanisms triggered by tumor cells or the derivatives are believed to be a major obstacle. We studied the role of DC-derived IL-10 and its negative impact on vaccine efficacy in mouse models. Liver tumor cells were injected via the portal vein, giving rise to disseminated intrahepatic tumors, or s.c. to form solid but extrahepatic tumors. Bone marrow-derived DCs were generated from normal or IL-10-deficient mice and used as the vector to deliver tumor Ags. We demonstrate here that DCs devoid of IL-10, a potent immunosuppressive cytokine, are superior over conventional DCs in triggering antitumor immunity. The IL-10–/–DCs were highly immunogenic, expressed enhanced levels of surface MHC class II molecules, and secreted increased amounts of Th1-related cytokines. By inducing tumor-specific killing and through the establishment of immunological memory, the vaccines delivered by IL-10–/–DCs could evoke strong therapeutic and protective immunity against hepatocellular carcinoma in the mouse models. These findings will have great clinical impact once being translated into the treatment of malignant, and potentially infectious, diseases in humans.
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 Hong Kong Research Grant Council Grants RGC HKU 7246/01M and 7291/02M and grants from the Hong Kong University Research Grant Committee. Y.-X.C. is a Cheng Yu Tong Visiting Scholar from Xiang Ya School of Medicine, Central South University, Hunan, China.
2 Current address: Deparment of Immunology, School of Basic Medical Sciences, Xiang Ya School of Medicine, Central South University, Hunan, China.
3 Address correspondence and reprint requests to Dr. Fang-Ping Huang, Room 333, 3/F, Block L, Molecular Genetics and Rheumatology Section, Imperial College Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London, W12 ONN U.K. E-mail address: fp.huang{at}imperial.ac.uk
4 Abbreviations used in this paper: TAA, tumor-associated Ag; DC, dendritic cell; HCC, hepatocellular carcinoma; IL-10–/–DC, DC generated from IL-10 knockout mice; SPC, spleen cells; WtDC, DC generated from wild-type control mice; PV, portal vein.
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