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Necrotic Tumor Cell Death In Vivo Impairs Tumor-Specific Immune Responses¹

Jaba Gamrekelashvili^*, Christine Krüger^*, Reinhard von Wasielewski, Matthias Hoffmann, Katharina M. Huster, Dirk H. Busch, Michael P. Manns^*, Firouzeh Korangy^2,* and Tim F. Greten^2,*

^* Department of Gastroenterology, Hepatology and Endocrinology, Department of Pathology, Departments of Visceral and Transplantation Surgery, Hannover Medical School, Hannover, Germany; and Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany

The manner in which cells die is believed to have a major impact on the nature of immune responses to their released Ags. In this study, we present the first direct analysis of tumor-specific immune responses to in vivo occurring tumor cell death through apoptosis or necrosis. Mice bearing thymidine kinase-transfected tumors were treated either with ganciclovir to induce tumor cell apoptosis in vivo or a vascular targeting agent, ZD6126, to induce tumor cell necrosis in vivo. In contrast to tumor apoptosis, induction of necrosis reduced the frequency and impaired the function of tumor-specific CD8⁺ T cells. Adoptive transfer of lymphocytes from mice with apoptotic tumors into tumor-challenged mice resulted in a significant tumor protection, which was absent when splenocytes were transferred from mice with necrotic tumors. Anti-CD40 treatment reversed impaired Ag-specific CD8⁺ T cell responses in these mice. These observations have not only fundamental importance for the development of immunotherapy protocols but also help to understand the underlying mechanism of in vivo immune responses to tumor cell death.

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 T.F.G. and F.K. are supported by grants from American Institute for Cancer Research (04-269) and Fresenius Stiftung. D.H.B. is supported by a grant from Deutsche Forschungsgemeinschaft (SFB 456).

² T.F.G. and F.K. are cosenior authors on this publication.

³ Address correspondence and reprint requests to Dr. Tim F. Greten, Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Carl Neuberg Strasse 1, 30625 Hannover, Germany; E-mail address: greten.tim{at}mh-hannover.de or Dr. Firouzeh Korangy, Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Carl Neuberg Strasse 1, 30625 Hannover, Germany; E-mail address: Korangy.Firouzeh{at}mh-hannover.de

⁴ Abbreviations used in this paper: TK, thymidine kinase; DLN, draining lymph node; GCV, ganciclovir.