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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0802322v1 183/3/1828    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Thomas, D. L. Articles by Roy, E. J. PubMed PubMed Citation Articles by Thomas, D. L. Articles by Roy, E. J.

Recurrence of Intracranial Tumors following Adoptive T Cell Therapy Can Be Prevented by Direct and Indirect Killing Aided by High Levels of Tumor Antigen Cross-Presented on Stromal Cells¹

Diana L. Thomas^*, Miri Kim^*, Natalie A. Bowerman, Samanthi Narayanan, David M. Kranz, Hans Schreiber and Edward J. Roy^2,*,

^* Neuroscience Program, Department of Biochemistry, and Department of Pathology, University of Illinois, Urbana-Champaign, Urbana, IL 61801; and Department of Pathology, University of Chicago, Chicago, IL 60637

Elimination of peripheral tumors by adoptively transferred tumor-specific T cells may require killing of cancer cells and tumor stromal cells. Tumor Ags are cross-presented on stromal cells, resulting in direct cytotoxic T cell (CTL) killing of both Ag-expressing cancer cells and stromal cells. Indirect killing of Ag loss variant cells also occurs. We show here that similar processes occur in a brain tumor stromal environment. We used murine cancer cell lines that express high or low levels of a peptide Ag, SIYRYYGL (SIY), recognized by transgenic 2C CD8⁺ T cells. The two cell lines are killed with equivalent efficiency by 2C T cells in vitro. Following adoptive transfer of 2C T cells into mice with established SIY-Hi or SIY-Lo brain tumors, tumors of both types regressed, but low-Ag-expressing tumors recurred. High-Ag-expressing tumors contained CD11b⁺ cells cross-presenting SIY peptide and were completely eliminated by 2C T cells. To further test the role of cross-presentation, RAG1^–/– H-2^b mice were infused with H-2^k tumor cells expressing high levels of SIY peptide. Adoptively transferred 2C T cells are able to kill cross-presenting H-2^b stromal cells but not H-2^k tumor cells. In peripheral models, this paradigm led to a small static tumor. In the brain, activated 2C T cells were able to kill cross-presenting CD11b⁺ cells and completely eliminate the H-2^k tumors in most mice. Targeting brain tumor stroma or increasing Ag shedding from tumor cells to enhance cross-presentation may improve the clinical success of T cell adoptive therapies.

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 by a James S. McDonnell Foundation grant (to D.M.K. and E.J.R.) and National Institutes of Health Grant R21 CA110010 (to E.J.R.).

² Address correspondence and reprint requests to Dr. Edward J. Roy, Department of Pathology, University of Illinois at Urbana-Champaign, 506 S. Matthews Avenue, Urbana, IL 61801. E-mail address: eroy{at}illinois.edu

³ Abbreviations used in this paper: ALV, Ag loss variant; eGFP, enhanced GFP; MHC I, MHC class I; PI, propidium iodide.

⁴ The online version of this article contains supplemental material.