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J. Microbiol. Biotechnol. 2006; 16(12): 1919-1927

Published online December 28, 2006

Copyright © The Korean Society for Microbiology and Biotechnology.

MethA Fibrosarcoma Cells Expressing Membrane-Bound Forms of IL-2 Enhance Antitumor Immunity

Sonn, Chung Hee , Hee Ryung Yoon , In Ock Seong , Mi-Ra Chang , Yong Chan Kim , Han-Chul Kang 1, Seok-Cheol Suh 1 and Young Sang Kim 1*

Department of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon 305-764, Korea, 1Transgene Expression Team, National Institute of Agricultural Biotechnology, Rural Development Administration, Suwon 441-707, Korea

Abstract

Tumor cells genetically engineered to secrete cytokines are effective in tumor therapy, but various unexpected side effects are observed, which may result from the bulk activation of various bystander cells. In this study, we tested tumor vaccines expressing various membrane-bound forms of IL-2 (mbIL-2) on MethA fibrosarcoma cells to focus antitumor immune responses to CTL. Chimeric forms of IL-2 with whole CD4, deletion forms of CD4, and TNF were expressed on the tumor cell surface, respectively. Tumor clones expressing mbIL-2 or secretory form of IL-2 were able to support the cell growth of CTLL-2, an IL-2-dependent T cell line, and the proliferation of spleen cells from 2C TCR transgenic mice that are responsive to the $p2Ca/L^d$ MHC class I complex. Expression of mbIL-2 on tumor cells reduced the tumorigenicity of tumor cells, and the mice that once rejected the live IL-2/TNF tumor clone acquired systemic immunity against wild-type MethA cells. The IL-2/TNF clone was inferior to other clones in tumor formation, and superior in the stimulation of the CD8+ T cell population in vitro. These results suggest that the IL-2/TNF clone is the best tumor vaccine, and may stimulate CD8+ T cells by direct priming. Expression of IL-2/TNF on tumor cells may serve as an effective gene therapy method to ameliorate the side effects encountered in the recombinant cytokine therapy and the conventional cytokine gene therapy using the secretory form of IL-2.

Keywords: IL-2, membrane-bound form, antitumor immunity, tumor vaccine, direct priming, CTL