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Anti-CD40 Conditioning Enhances the T_CD8 Response to a Highly Tolerogenic Epitope and Subsequent Immunotherapy of Simian Virus 40 T Antigen-Induced Pancreatic Tumors¹

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

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

Rapid loss of adoptively transferred tumor-specific CD8⁺ T cells (T_CD8) following Ag recognition in the periphery and their limited accumulation within the tumor stroma reduces the effectiveness of T cell-based immunotherapy. To better understand the role of T_CD8 in the control of autochthonous tumors, we have used mice of the RIP1-Tag4 lineage that develop pancreatic β cell tumors due to expression of the SV40 large T Ag from the rat insulin promoter. We previously showed that the kinetics of functional T_CD8 tolerance varies toward two distinct epitopes derived from T Ag. Epitope I (₂₀₆SAINNYAQKL₂₁₅)-specific T_CD8 are rapidly deleted whereas T_CD8 targeting epitope IV (₄₀₄VVYDFLKC₄₁₁) persist over the lifetime of tumor-bearing animals. In this report, we show that the conditioning of tumor-bearing RIP1-Tag4 mice with agonistic anti-CD40 Ab induces extensive expansion of naive epitope I-specific TCR transgenic (TCR-I) T cells in this tolerogenic environment and delays their loss from the host. In addition, functional TCR-I T cells intensively infiltrate pancreatic tumors, resulting in increased survival of RIP1-Tag4 mice. These results suggest that a similar approach could effectively enhance T cell-based immunotherapies to cancer when targeting other highly tolerogenic epitopes.

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 CA-34196 (to B.B.K.); and American Cancer Society Research Scholar Grant 04-059-01-LIB (to T.D.S.).

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

³ Address correspondence and reprint requests to Dr. Todd D. Schell, Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033. E-mail address: tschell{at}psu.edu

⁴ Abbreviations used in this paper: T_CD8, CD8⁺T cell; DAPI, 4',6'-diamidino-2-phenylindole; Db/Flu, H-2D^b/Flu NP epitope; Db/I, H-2D^b/T Ag epitope I; Flu, influenza virus; GP33, glycoprotein 33; NP, nucleoprotein; PD-L1, programmed death ligand 1; RT4, RIP1-Tag4; TCR-I, TCR transgenic T_CD8 specific for T Ag epitope I.

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