Murine Model of Prostate Cancer Despite Efficient Initial Priming in a Primary Tolerization of Tumor-Specific T Cells

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. T he context in which an APC presents Ag plays a key role in determining the fate of T cells. Dendritic cells (DCs) 3 can be extremely effective in priming naive T cells upon TCR engagement of cognate Ag MHC (1). Depending on the mat-uration state of the DC, naive T cells can differentiate into efficient CTLs or undergo tolerance and/or deletion. Evidence suggests that tolerogenic DCs correspond to resting DCs, expressing low levels of both MHC and costimulatory molecules, whereas immunogenic DCs have encountered maturation stimuli to up-regulate expression of MHC and costimulatory molecules and increase IL-12 secretion (2, 3). Tolerogenic DCs may also arise to due interactions with regulatory cells (4, 5). Various stimuli, such as pathogen by-products that stimulate TLRs (6, 7), activated CD4 ϩ T cells (8), and even CD8 ϩ T cells (9) can provide the appropriate signals to activate tolerogenic DCs. When trying to elicit an antitumor response, several regulatory mechanisms may exist. Among these are the secretion of immu-nosuppressive factors …