Kiniwa Yukiko, Miyahara Yoshihiro, Wang Helen Y, Peng Weiyi, Peng Guangyong, Wheeler Thomas M, Thompson Timothy C, Old Lloyd J, Wang Rong-Fu
Department of Pathology, The Center for Cell and Gene Therapy, Baylor Colleg of Medicine, Houston, Texas 77030, USA.
Clin Cancer Res. 2007 Dec 1;13(23):6947-58. doi: 10.1158/1078-0432.CCR-07-0842.
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.
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.
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.
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.
尽管在几种癌症类型中已显示CD4(+)CD25(+)调节性T（Treg）细胞比例升高，但关于前列腺癌中CD8(+) Treg细胞的存在及功能却知之甚少。在本研究中，我们调查了前列腺肿瘤来源的CD8(+) Treg细胞及其功能。
从前列腺癌患者的新鲜肿瘤标本中获取肿瘤浸润淋巴细胞（TIL），并进行表型和抑制功能分析。特别是，我们研究了CD8(+) Treg细胞在前列腺癌中的作用和功能。
我们发现，大多数（70%）前列腺TIL中可能存在高比例的CD4(+)CD25(+) T细胞。值得注意的是，CD4(+)和CD8(+) T细胞亚群均具有强大的抑制活性。T细胞克隆和荧光激活细胞分选分析表明，除了先前已知的CD4(+)CD25(+) Treg细胞外，还存在表达FoxP3并抑制幼稚T细胞增殖的CD8(+)CD25(+) Treg细胞克隆。这些CD8(+) Treg细胞主要通过细胞接触依赖性机制抑制幼稚T细胞增殖。重要的是，人Toll样受体8（TLR8）信号传导可逆转CD8(+) Treg细胞的抑制功能。
我们的研究表明，与CD4(+)CD25(+) Treg细胞一样，前列腺肿瘤来源的TIL中存在的CD8(+) Foxp3(+) Treg细胞可抑制免疫反应，且其抑制功能可由TLR8配体调节，这增加了通过TLR8配体操纵Treg细胞功能可能提高前列腺癌患者免疫治疗疗效的可能性。
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