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Suppression of an Already Established Tumor Growing through Activated Mucosal CTLs Induced by Oral Administration of Tumor Antigen with Cholera Toxin¹

Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan

Priming of CTLs at mucosal sites, where various tumors are originated, seems critical for controlling tumors. In the present study, the effect of the oral administration of OVA plus adjuvant cholera toxin (CT) on the induction of Ag-specific mucosal CTLs as well as their effect on tumor regression was investigated. Although OVA-specific TCRs expressing lymphocytes requiring in vitro restimulation to gain specific cytotoxicity could be detected by OVA peptide-bearing tetramers in both freshly isolated intraepithelial lymphocytes and spleen cells when OVA was orally administered CT, those showing direct cytotoxic activity without requiring in vitro restimulation were dominantly observed in intraepithelial lymphocytes. The magnitude of such direct cytotoxicity at mucosal sites was drastically enhanced after the second oral administration of OVA with intact whole CT but not with its subcomponent, an A subunit (CTA) or a B subunit (CTB). When OVA plus CT were orally administrated to C57BL/6 mice bearing OVA-expressing syngeneic tumor cells, E.G7-OVA, in either gastric tissue or the dermis, tumor growth was significantly suppressed after the second oral treatment; however, s.c. or i.p. injection of OVA plus CT did not show any remarkable suppression. Those mucosal OVA-specific CTLs having direct cytotoxicity expressed CD8β but not CD8, suggesting that they originated from thymus-educated cells. Moreover, the infiltration of such OVA-specific CD8⁺ CTLs was observed in suppressed tumor tissues. These results indicate that the growth of ongoing tumor cells can be suppressed by activated CD8β CTLs with tumor-specific cytotoxicity via an orally administered tumor Ag with a suitable mucosal adjuvant.

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 in part by Grants-in-Aid for Young Scientists from the Japan Society for the Promotion of Sciences, from the Ministry of Education, Science, Sport, and Culture, from the Ministry of Health and Labor and Welfare, Japan, and from the Promotion and Mutual Aid Corporation for Private Schools of Japan.

² Address correspondence and reprint requests to Dr. Hidemi Takahashi, Department of Microbiology and Immunology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan. E-mail address: htkuhkai{at}nms.ac.jp

³ Abbreviations used in this paper: IEL, intraepithelial lymphocyte; CT, cholera toxin; CTA, CT A subunit (toxic); CTB, CT B subunit (nontoxic); DC, dendritic cell; GM, monosialoganglioside; Hp, Helicobacter pylori; LPL, lamina propria lymphocyte; MadCAM-1, mucosal addressin cell-adhesion molecule-1; OVA-CT, CT-conjugated OVA; PP, Peyer’s patch; rVV, recombinant vaccinia virus; SC, spleen cell; Tg, transgenic; TIL, tumor-infiltrating lymphocyte.