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* Tumor Immunity and Tolerance Section, Laboratory of Molecular Immunoregulation, National Cancer Institute, National Institutes of Health, Frederick, MD 21701;
Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY 13210;
Laboratory of Cell-Mediated Immunity, Clinical Services Program, SAIC-Frederick, Frederick, MD 21701; and
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
In this report, we studied T cell responses to a prostate cancer Ag by adoptively transferring tumor Ag-specific T cells into prostate tumor-bearing mice. Our findings demonstrate that CD8+ T cells initially encountered tumor Ag in the lymph node and underwent an abortive proliferative response. Upon isolation from the tumor, the residual tumor-specific T cells were functionally tolerant of tumor Ag as measured by their inability to degranulate and secrete IFN-
and granzyme B. We next sought to determine whether providing an ex vivo-matured, peptide-pulsed dendritic cell (DC) vaccine could overcome the tolerizing mechanisms of tumor-bearing transgenic adenocarcinoma of the mouse prostate model mice. We demonstrate that tumor Ag-specific T cells were protected from tolerance following provision of the DC vaccine. Concurrently, there was a reduction in prostate tumor size. However, even when activated DCs initially present tumor Ag, T cells persisting within the tolerogenic tumor environment gradually lost Ag reactivity. These results suggest that even though a productive antitumor response can be initiated by a DC vaccine, the tolerizing environment created by the tumor still exerts suppressive effects on the T cells. Furthermore, our results demonstrate that when trying to elicit an effective antitumor immune response, two obstacles must be considered: to maintain tumor Ag responsiveness, T cells must be efficiently primed to overcome tumor Ag presented in a tolerizing manner and protected from the suppressive mechanisms of the tumor microenvironment.
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 research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. This work is in partial fulfillment of the degree of Doctor of Philosophy at State University of New York, Upstate Medical University for Michael J. Anderson.
2 Address correspondence and reprint requests to Dr. Arthur A. Hurwitz, Tumor Immunity and Tolerance Section, Laboratory of Molecular Immunoregulation, National Cancer Institute, National Institutes of Health, Frederick, MD 21701.
3 Abbreviations used in this paper: DC, dendritic cell; LN, lymph node; TRAMP, transgenic adenocarcinoma of the mouse prostate; pDLN, prostate draining LN; nDLN, nondraining LN; WT, wild type; ATx, adoptive transfer.
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