Peripheral T-Cell Tolerance Associated with Prostate Cancer Is Independent from CD4+CD25+ Regulatory T Cells

Abstract

CD4 + CD25 + Foxp3 + regulatory T cells (Treg) are thought to suppress the natural and vaccine-induced immune response against tumor-associated antigens (TAA). Here, we show that Treg accumulate in tumors and tumor-draining lymph nodes of aging transgenic adenocarcinoma of the mouse prostate (TRAMP) male mice, which spontaneously develop prostate cancer. TAA overexpression and disease progression associate also with induction of TAA-specific tolerance. TAA-specific T cells were found in the lymphoid organs of tumor-bearing mice. However, they had lost the ability to release IFN-; and kill relevant targets. Neither in vivo depletion of Treg by PC61 monoclonal antibody followed by repeated vaccinations with antigen-pulsed dendritic cells nor the combined treatment with 1-methyl-L-tryptophan inhibitor of the enzyme indoleamine 2,3-dyoxigenase, PC61 antibody, and dendritic cell vaccination restored the TAA-specific immune response. Treg did not seem to control the early phases of tolerance induction, as well. Indeed, depletion of Treg, starting at week 6, the age at which TRAMP mice are not yet tolerant, and prolonged up to week 12, did not avoid tolerance induction. A similar accumulation of Treg was found in the lymph nodes draining the site of dendritic cell vaccination both in TRAMP and wild-type animals. Hence, we conclude that Treg accrual is a phenomenon common to the sites of an ongoing immune response, and in TRAMP mice in particular, Treg are dispensable for induction of tumor-specific tolerance. [Cancer Res 2008;68(1):292-300]

Apoptotic cells attenuate fulminant hepatitis by priming Kupffer cells to produce interleukin-10 through membrane-bound TGF-β

“…28 An anti-CD25 Ab (PC 61) was used to deplete regulatory T cells from mice at 24 hours before LPS/D-GalN injection. 29 Cytochalasin B, a blocker of microfilament formation, was used to inhibit phagocytosis of macrophages and DCs. 30 For adoptive cell transfer, mice were treated with GdCl 3 , and then received portal vein (p.v.)…”

Modulators of Arginine Metabolism Do Not Impact on Peripheral T-Cell Tolerance and Disease Progression in a Model of Spontaneous Prostate Cancer

“…8A) and autopsy (not shown) did not evidence sign of drug-related toxicity. At microscopic examination, the prostate of most of the vehicle-treated animals was characterized by enlarged acini presenting a well-differentiated microinvasive PC (33). The average disease score for these animals was 3.5 AE 0.71 (Supplementary Fig.…”

Cancer vaccines inducing antibody production: more pros than cons

“…It has been suggested that Tregs especially hamper the breakthrough of most anticancer vaccination approaches [97]. On the other hand, TAA-specific T-cell tolerance being independent on Treg participation has been demonstrated by depletion experiments of the CD4 + CD25 + population in vivo in mice [98]. Even if the role of Tregs is not ultimately clear, evidence that they might be exploited by reprogramming represents an intriguing concept.…”