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

T cells are in general tolerant of prostate-specific tumor antigens. That prostate tumor tissue makes transforming growth factor-beta (TGF beta) 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 TGF beta 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 TGF beta through T-cell-specific transgenic expression of a dominant-negative variant of the TGF beta receptor II (dnTGFRII), was analyzed after adoptive transfer into prostate OVA-expressing transgenic ( POET) mice. The role of TGFb beta 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. TGF beta-resistant CD8(+) T cells proliferated more and produced IFN gamma more readily after OVA stimulation in vitro. OVA-specific T cells did not damage the prostate gland of POET mice irrespective of TGF beta responsiveness. However, ex vivo activation facilitated entry of TGF beta-insensitive T cells into the prostate and was associated with prostate tissue damage. Early tumor progression was delayed in TRAMP mice that carried endogenous TGF beta-insensitive T cells. Together, these results suggest that TGF beta-signaling represses CD8(+) T-cell responses to a prostate-specific antigen. TGF beta-mediated repression of T-cell function may include production of IFN gamma which is known to contribute to tumor immunosurveillance. Laboratory Investigation ( 2009) 89, 142-151; doi: 10.1038/labinvest.2008.123; published online 15 December 2008