CD8+ Foxp3+ Regulatory T Cells Mediate Immunosuppression in Prostate Cancer

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Abstract
Purpose: Although elevated proportions of CD4+CD25+ regulatory T (Treg) cells have been shown in several types of cancers, very little is known about the existence and function of CD8+ Treg cells in prostate cancer. In this study, we investigated prostate tumor–derived CD8+ Treg cells and their function. Experimental Design: Tumor-infiltrating lymphocytes (TIL) from fresh tumor specimens of patients with prostate cancer were generated and subjected to phenotypic and suppressive function analyses. In particular, we investigated the role and function CD8+ Treg cells in prostate cancer. Results: We show that high percentages of CD4+CD25+ T cells are probably present in the majority (70%) of prostate TILs. Remarkably, both CD4+ and CD8+ T-cell subpopulations possessed potent suppressive activity. T-cell cloning and fluorescence-activated cell sorting analyses showed the presence of CD8+CD25+ Treg cell clones that expressed FoxP3 and suppressed naïve T-cell proliferation, in addition to the previously known CD4+CD25+ Treg cells. These CD8+ Treg cells suppressed naïve T-cell proliferation mainly through a cell contact–dependent mechanism. Importantly, the suppressive function of CD8+ Treg cells could be reversed by human Toll-like receptor 8 (TLR8) signaling. Conclusion: Our study shows that like CD4+CD25+ Treg cells, CD8+ Foxp3+ Treg cells present in prostate tumor–derived TILs suppress immune responses and that their suppressive function can be regulated by TLR8 ligands, raising the possibility that the manipulation of Treg cell function by TLR8 ligands could improve the efficacy of immunotherapy for prostate cancer patients.