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

Abstract

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-γ 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.

High-Avidity T Cells Are Preferentially Tolerized in the Tumor Microenvironment

“…We show that unlike lower avidity TCR lo T cells, the higher avidity TCR hi T cells that persisted in the TME lost their ability to produce IFN-γ and to mobilize CD107a, hallmarks of tolerance. These data confirm our previous report demonstrating loss of CTL function among tumor-specific CD8 + T cells that infiltrate prostate tumors (21). Morgan and colleagues also reported that higher avidity, Flu-HA-specific T cells were more readily tolerized than lower avidity T cells with identical specificity (22).…”

“…However, the failure of many patients to develop long-term tumor control may be, in part, due to tolerization of transferred T cells (18). Our lab has reported that in an experimental model of prostate cancer, tumor antigen-specific CD8 + T cells become tolerized after infiltrating tumor tissue (19–21). One previous study suggested that recognition of a xenogeneic, tumor-associated antigen by higher avidity T cells leads to increased susceptibility to tolerization (22).…”

The immunocytokine NHS-IL12 as a potential cancer therapeutic

“…Many cancer vaccines that were specifically designed to induce strong tumor-specific T-cell responses are in development [45]. However, effector T cells can still be inactivated upon entering the immunosuppressive tumor microenvironment [46]. Pairing a cancer vaccine with NHS-IL12 treatment might allow for the vaccine-induced T cells to better infiltrate the tumor and remain active by virtue of their exposure to NHS-IL12.…”

Immunotherapy for Prostate Cancer: An Emerging Treatment Modality

“…Although the prostate glands of patients with cancer contain a CD4 and CD8 T-cell infiltrate, phenotypic analyses of these cells 8,64,65 and numerous murine studies 66–70 are consistent with the notion that these infiltrating cells are nonfunctional in lytic function. Several T-cell molecules seem to contribute to this lack of function, most notably CTLA4, which interacts with B7 family molecules on antigen-presenting cells to downregulate T-cell function.…”