Melanoma-Educated CD14+ Cells Acquire a Myeloid-Derived Suppressor Cell Phenotype through COX-2-Dependent Mechanisms
Melanoma-Educated CD14+ Cells Acquire a Myeloid-Derived Suppressor Cell Phenotype through COX-2-Dependent Mechanisms
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DOI：
10.1158/0008-5472.can-12-4115
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发表时间：
2013-07-01
期刊：
影响因子：
11.2
通讯作者：
Kiessling, Rolf
中科院分区：
文献类型：
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作者：
Mao, Yumeng;Poschke, Isabel;Kiessling, Rolf
肿瘤可通过多种细胞免疫调节剂，如调节性T细胞、肿瘤相关巨噬细胞和髓源性抑制细胞（MDSC）来抑制宿主免疫系统。在晚期黑色素瘤患者的外周血中，存在CD14(+)HLA - DRlo/- MDSC的积聚，其以STAT - 3依赖的方式在体外抑制自体T细胞。然而，这种效应背后的确切机制基础尚不清楚，特别是关于MDSC的诱导机制是否依赖于黑色素瘤细胞与CD14(+)细胞的细胞 - 细胞接触。在此，我们发现早期传代的人黑色素瘤细胞可诱导CD14(+)单核细胞发生表型变化，使其类似于晚期黑色素瘤患者中所描述的MDSC。这些类MDSC细胞可强效抑制自体T细胞增殖和干扰素 - γ的产生。值得注意的是，髓系抑制功能的诱导需要单核细胞与肿瘤细胞之间的接触或紧密接近。此外，这种诱导在很大程度上依赖于环氧合酶 - 2（COX - 2）的产生，因为在这些类MDSC细胞中对其进行抑制会限制它们抑制T细胞功能的能力。我们用从晚期黑色素瘤患者中分离出的CD14(+)细胞证实了我们的发现，这些细胞以依赖前列腺素E2（PGE(2)）、STAT - 3和超氧化物的方式抑制自体T细胞。实际上，PGE(2)足以赋予单核细胞在体外抑制自体T细胞增殖和干扰素 - γ产生的能力。总之，我们的结果揭示了在人黑色素瘤的肿瘤微环境中MDSC的免疫抑制是如何启动的。（C）2013美国癌症研究协会
Tumors can suppress the host immune system by employing a variety of cellular immune modulators, such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells (MDSC). In the peripheral blood of patients with advanced stage melanoma, there is an accumulation of CD14(+)HLA-DRlo/- MDSC that suppress autologous T cells ex vivo in a STAT-3-dependent manner. However, a precise mechanistic basis underlying this effect is unclear, particularly with regard to whether the MDSC induction mechanism relies on cell-cell contact of melanoma cells with CD14(+) cells. Here, we show that early-passage human melanoma cells induce phenotypic changes in CD14(+) monocytes, leading them to resemble MDSCs characterized in patients with advanced stage melanoma. These MDSC-like cells potently suppress autologous T-cell proliferation and IFN-gamma production. Notably, induction of myeloid-suppressive functions requires contact or close proximity between monocytes and tumor cells. Further, this induction is largely dependent on production of cyclooxygenase-2 (COX-2) because its inhibition in these MDSC-like cells limits their ability to suppress T-cell function. We confirmed our findings with CD14(+) cells isolated from patients with advanced stage melanoma, which inhibited autologous T cells in a manner relying up prostaglandin E2 (PGE(2)), STAT-3, and superoxide. Indeed, PGE(2) was sufficient to confer to monocytes the ability to suppress proliferation and IFN-gamma production by autologous T cells ex vivo. In summary, our results reveal how immune suppression by MDSC can be initiated in the tumor microenvironment of human melanoma. (C) 2013 AACR.