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CD8⁺ T Cells Targeting a Single Immunodominant Epitope are Sufficient for Elimination of Established SV40 T Antigen-Induced Brain Tumors¹

Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033

Immunotherapy of established solid tumors is rarely achieved, and the mechanisms leading to success remain to be elucidated. We previously showed that extended control of advanced-stage autochthonous brain tumors is achieved following adoptive transfer of naive C57BL/6 splenocytes into sublethally irradiated line SV11 mice expressing the SV40 T Ag (T Ag) oncoprotein, and was associated with in vivo priming of CD8⁺ T cells (T_CD8) specific for the dominant epitope IV (T Ag residues 404–411). Using donor lymphocytes derived from mice that are tolerant to epitope IV or a newly characterized transgenic mouse line expressing an epitope IV-specific TCR, we show that epitope IV-specific T_CD8 are a necessary component of the donor pool and that purified naive epitope IV-specific T_CD8 are sufficient to promote complete and rapid regression of established tumors. While transfer of naive TCR-IV cells alone induced some initial tumor regression, increased survival of tumor-bearing mice required prior conditioning of the host with a sublethal dose of gamma irradiation and was associated with complete tumor eradication. Regression of established tumors was associated with rapid accumulation of TCR-IV T cells within the brain following initial priming against the endogenous T Ag in the peripheral lymphoid organs. Additionally, persistence of functional TCR-IV cells in both the brain and peripheral lymphoid organs was associated with long-term tumor-free survival. Finally, we show that production of IFN-, but not perforin or TNF-, by the donor lymphocytes is critical for control of autochthonous brain tumors.

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 Grants CA-25000 and CA-24694 from the National Cancer Institute/National Institutes of Health and by American Cancer Society Research Scholar Grant 04-059-01-LIB.

² Current address: Department of Biological Sciences, Messiah College, Grantham, PA 17027.

³ Current address: University of Pennsylvania, Philadelphia, PA 19104.

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

⁵ Abbreviations used in this paper: B6, C57BL/6; CLN, cervical lymph node; gB, glycoprotein B; ICS, intracellular cytokine staining; KO, knockout; T Ag, SV40 T antigen; T_CD8, CD8⁺ T cell; WT, wild-type.