Myeloid derived suppressor cells (MDSC) suppress the ability of cytotoxic T cells to attack and clear tumor cells from the body. The active form of vitamin D, 1,25 dihydroxyvitamin D (1,25(OH)2D), regulates myeloid cell biology and previous research showed that in mouse models 1,25(OH)2D reduced the tumor level of CD34+ cells, an MDSC precursor, and reduced metastasis. We tested whether MDSC are vitamin D target cells by examining granulocytic- (G-MDSC) and monocytic (M-MDSC) MDSC from tumors, spleen, and bone marrow. Vitamin D receptor (VDR) mRNA levels are low in MDSC from bone marrow and spleen but are 20-fold higher in tumor MDSC. At all sites, M-MDSC have 4-fold higher VDR mRNA expression than G-MDSC. Bone marrow MDSC were induced to differentiate in vitro into tumor MDSC-like cells by treating with IFN-γ, IL-13, and GM-CSF for 48 h. This treatment significantly elevated Arg1 and Nos2 levels, activated the T cell-suppressive function of MDSC, increased VDR expression 50-fold, and made the MDSC responsive to 1,25(OH)2D treatment. Importantly, 1,25(OH)2D treatment reduced the T cell suppressive capacity of cytokine-induced total MDSC and M-MDSC by ≥70 % and tumor-derived M-MDSC by 30-50 %. Consistent with this finding, VDR deletion (KO) increased T cell suppressive function of in vitro M-MDSC by 30 % and of tumor-derived M-MDSC by 50 % and G-MDSC by 400 %. VDR KO did not alter Nos2 mRNA levels but significantly increased Arg1 mRNA levels in tumor M-MDSC by 100 %. In contrast, 1,25(OH)2D treatment reduced nitric oxide production in both in vitro derived M- and G- MDSC. The major finding of this study is that 1,25(OH)2D signaling through the VDR decreases the immunosuppressive capability of MDSC. Collectively, our data suggest that activation of vitamin D signaling could be used to suppress MDSC function and release a constraint on T-cell mediated clearance of tumor cells.

中文翻译：

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1α，25二羟基维生素D（1,25（OH）2D）抑制髓样来源的抑制细胞（MDSC）的T细胞抑制功能。

骨髓来源的抑制细胞（MDSC）抑制细胞毒性T细胞攻击和清除体内肿瘤细胞的能力。维生素D的活性形式1,25二羟基维生素D（1,25（OH）2D）调节骨髓细胞生物学，先前的研究表明，在小鼠模型中1,25（OH）2D降低了CD34 +细胞的肿瘤水平， MDSC的前体，并减少了转移。我们通过检查来自肿瘤，脾脏和骨髓的粒细胞（G-MDSC）和单核细胞（M-MDSC）MDSC来测试MDSC是否为维生素D靶细胞。骨髓和脾脏的MDSC中的维生素D受体（VDR）mRNA水平低，而肿瘤MDSC中的维生素D受体（VDR）mRNA水平高20倍。在所有位点，M-MDSC的VDR mRNA表达比G-MDSC高4倍。通过用IFN-γ，IL-13和GM-CSF处理48小时，诱导骨髓MDSC在体外分化为肿瘤MDSC样细胞。该处理显着提高了Arg1和Nos2的水平，激活了MDSC的T细胞抑制功能，使VDR表达增加了50倍，并使MDSC对1,25（OH）2D处理产生响应。重要的是，1,25（OH）2D处理将细胞因子诱导的总MDSC和M-MDSC的T细胞抑制能力降低了≥70％，并将肿瘤来源的M-MDSC降低了30-50％。与此发现一致，VDR缺失（KO）将体外M-MDSC的T细胞抑制功能提高了30％，将肿瘤来源的M-MDSC的T细胞抑制功能提高了50％，将G-MDSC的T细胞抑制功能提高了400％。VDR KO不会改变Nos2 mRNA水平，但会显着增加肿瘤M-MDSC中Arg1 mRNA水平100％。相反，在体外衍生的M-和G- MDSC中，1,25（OH）2D处理均减少了一氧化氮的产生。这项研究的主要发现是，通过VDR传递的25（OH）2D信号会降低MDSC的免疫抑制能力。总体而言，我们的数据表明，维生素D信号的激活可用于抑制MDSC功能并释放对T细胞介导的肿瘤细胞清除的限制。