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Early Immunization Induces Persistent Tumor-Infiltrating CD8⁺ T Cells against an Immunodominant Epitope and Promotes Lifelong Control of Pancreatic Tumor Progression in SV40 Tumor Antigen Transgenic Mice¹

Pavel Otahal^2,*, Todd D. Schell^*, Sandra C. Hutchinson^3,*, Barbara B. Knowles and Satvir S. Tevethia^4,*

^* Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033; and The Jackson Laboratory, Bar Harbor, ME 04609

The ability to recruit the host’s CD8⁺ T lymphocytes (T_CD8) against cancer is often limited by the development of peripheral tolerance toward the dominant tumor-associated Ags. Because multiple epitopes derived from a given tumor Ag (T Ag) can be targeted by T_CD8, vaccine approaches should be directed toward those T_CD8 that are more likely to survive under conditions of persistent Ag expression. In this study, we investigated the effect of peripheral tolerance on the endogenous T_CD8 response toward two epitopes, designated epitopes I and IV, from the SV40 large T Ag. Using rat insulin promoter (RIP) 1-Tag4 transgenic mice that express T Ag from the RIP and develop pancreatic insulinomas, we demonstrate that epitope IV- but not epitope I-specific T_CD8 are maintained long term in tumor-bearing RIP1-Tag4 mice. Even large numbers of TCR-transgenic T cells specific for epitope I were rapidly eliminated from RIP1-Tag4 mice after adoptive transfer and recognition of the endogenous T Ag. Importantly, immunization of RIP1-Tag4 mice at 5 wk of age against epitope IV resulted in complete protection from tumor progression over a 2-year period despite continued expression of T Ag in the pancreas. This extensive control of tumor progression was associated with the persistence of functional epitope IV-specific T_CD8 within the pancreas for the lifetime of the mice without the development of diabetes. This study indicates that an equilibrium is reached in which immune surveillance for spontaneous cancer can be achieved for the lifespan of the host while maintaining normal organ function.

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 study was supported by National Cancer Institute/National Institutes of Health Grants CA-25000 (to S.S.T.) and PO3 CA-34196 (to B.B.K.) and American Cancer Society Research Scholar Grant 04-059-01-LIB (to T.D.S.). S.C.H. was supported by National Cancer Institute Training Grant T32 CA60395.

² Current address: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic.

³ Current address: Department of Biology, Sinclair Community College, Dayton, OH 45402.

⁴ Address correspondence and reprint requests to Dr. Satvir S. Tevethia, Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033. E-mail address: sst1{at}psu.edu

⁵ Abbreviations used in this paper: T_CD8, CD8⁺ T lymphocyte; B6, C57BL/6; Db, H-2D^b; Db/I, Db epitope I; Flu, influenza virus; gB, glycoprotein B; HA, hemagglutinin; Kb, H-2K^b; Kb/IV, Kb epitope IV; LCMV, lymphocytic choriomeningitis virus; NP, nucleoprotein; RIP, rat insulin promoter; T Ag, tumor Ag.

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