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Carbonic Anhydrase II Is a Tumor Vessel Endothelium–Associated Antigen Targeted by Dendritic Cell Therapy

Authors' Affiliations: ¹ Departments of Advanced Medical Science and ² Laboratory Medicine and Divisions of ³ Cell Processing and ⁴ Molecular Biology, Institute of Medical Science, University of Tokyo; ⁵ Division of Dermatology, National Cancer Center, Central Hospital; ⁶ Division of Cellular Signaling, The Institute of Advanced Medical Science, Keio University School of Medicine, Tokyo, Japan; ⁷ Laboratory for Dendritic Cell Immunobiology, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Kanagawa, Japan; ⁸ Department of Dermatology, Yamanashi Medical University, Yamanashi, Japan; and ⁹ Department of Dermatology, Shinshu University School of Medicine, Matsumoto, Japan

Requests for reprints: Kenta Yoshiura, Department of Advanced Medical Science, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Phone: 81-3-5449-5772; Fax: 81-3-5449-5456; E-mail: yoshiura-gi{at}umin.ac.jp.

Tumor-associated antigens are promising candidates as target molecules for immunotherapy and a wide variety of tumor-associated antigens have been discovered through the presence of serum antibodies in cancer patients. We previously conducted dendritic cell therapy on 10 malignant melanoma patients and shrinkage or disappearance of metastatic tumors with massive necrosis occurred in two patients. In this study, we found a 29-kDa protein against which antibody was elicited by dendritic cell therapy in one of the two patients. Matrix-assisted laser desorption ionization-time of flight/mass spectrometry analysis of the protein isolated by two-dimensional electrophoresis combined with Western blots revealed that the 29-kDa protein was carbonic anhydrase II (CA-II). Immunohistochemistry of the tumors and normal tissues showed that CA-II was expressed in the tumor vessel but not in normal vessel endothelium. CA-II expression in tumor endothelium was observed as well in other cancers including esophageal, renal, and lung cancers. In an in vitro angiogenesis model, CA-II expression of normal human vein endothelial cells was significantly up-regulated when cells were cultured in the acidic and hypoxic conditions indicative of a tumor environment. These findings suggest that CA-II is a tumor vessel endothelium–associated antigen in melanoma and other cancers, and elicitation of serum anti–CA-II antibody by dendritic cell therapy may be associated with good clinical outcome including tumor reduction.

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