Transforming growth factor-β-mediated signaling in T lymphocytes impacts on prostate-specific immunity and early prostate tumor progression

Abstract

T cells are in general tolerant of prostate-specific tumor antigens. That prostate tumor tissue makes transforming growth factor-β (TGFβ) is thought to play a role in the induction of T-cell tolerance within the host and to contribute to tumor progression itself. Here we sought to investigate the influence of TGFβ signaling on prostate antigen-specific T-cell responses as well as prostate tumorogenesis in an autochthonous murine model of the disease. The response of naive and activated ovalbumin (OVA) antigen-specific T cells, which had been rendered incapable of responding to TGFβ through T-cell-specific transgenic expression of a dominant-negative variant of the TGFβ receptor II (dnTGFRII), was analyzed after adoptive transfer into prostate OVA-expressing transgenic (POET) mice. The role of TGFβ signaling in endogenous T cells in mice, which spontaneously form tumors, was also assessed by monitoring prostate tumor formation and progression in F1 progeny of productive matings between transgenic adenocarcinoma of the mouse prostate (TRAMP) and dnTGFRII mice. TGFβ-resistant CD8+ T cells proliferated more and produced IFNγ more readily after OVA stimulation in vitro. OVA-specific T cells did not damage the prostate gland of POET mice irrespective of TGFβ responsiveness. However, ex vivo activation facilitated entry of TGFβ-insensitive T cells into the prostate and was associated with prostate tissue damage. Early tumor progression was delayed in TRAMP mice that carried endogenous TGFβ-insensitive T cells. Together, these results suggest that TGFβ-signaling represses CD8+ T-cell responses to a prostate-specific antigen. TGFβ-mediated repression of T-cell function may include production of IFNγ, which is known to contribute to tumor immunosurveillance.