CVI Accepts, published online ahead of print on 4 November 2009

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Clin. Vaccine Immunol. doi:10.1128/CVI.00292-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Immunological factors relating to the antitumor effect of temozolomide chemo-immunotherapy in a murine glioma model

Tai-Gyu Kim, Chang-Hyun Kim, Jung-Sun Park, Sung-Dong Park, Chung Kwon Kim, Dong-Sup Chung, and Yong-Kil Hong^*

Catholic Research Institute of Medical Science, Department of Microbiology and Immunology and Neurosurgery, The Catholic University of Korea, Banpo-dong 505, Seocho-ku, Seoul 137-701; Department of Neurosurgery, Our Lady of Mercy Hospital College of Medicine, The Catholic University of Korea, 665 Bupyeong-dong, Bupyeong-gu, Incheon 403-720, South Korea; Dongguk University Research Institute of Biotechnology, Medical Science Research Center, Dongguk University School of Medicine, 814, Siksa-dong, Ilsandong-gu, Goyang-si, Gyenggi-do 410-773, South Korea

^* To whom correspondence should be addressed. Email: ykhong{at}catholic.ac.kr.

In this study, we investigated the potential of combined treatment with temozolomide (TMZ) chemotherapy and tumor antigen-pulsed dendritic cells (DCs) and the underlying immunological factors of TMZ chemo-immunotherapy in an intracranial GL26 glioma animal model. The combined treatment enhanced the tumor-specific immune responses and prolonged the survival more effectively than either single therapy in GL26 tumor-bearing animals. Apoptosis was induced in the tumor of animals by the treatment with TMZ. Calreticulin (CRT) surface exposure was detected by immunofluorescence staining in TMZ-treated GL26 cells. TMZ chemotherapy increased tumor antigen cross-priming from tumor cells, leading to cross-priming of tumor antigen-specific CD4⁺ T cells and CD8⁺ T cells. This chemotherapy appeared to suppress the frequency of CD4⁺ CD25⁺ regulatory T cells (Treg). Moreover, this combined therapy resulted in an increase of tumor infiltration of CD4⁺ and CD8⁺ T cells. Collectively, this study provides evidence that combined TMZ chemotherapy and DCs-based vaccines leads to the enhancement of antitumor immunity through increased tumor specific immune responses via the cross-priming of an apoptotic tumor cell death mediated by CRT exposure and the suppression of Treg in part. Therefore, CRT exposure, regulatory T cells, and cross-priming by TMZ chemotherapy may be an immunological factors related to enhancing antitumor effects of chemo-immunotherapy in experimental brain tumor.