Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-β-mediated suppressive activity on T lymphocytes
Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-β-mediated suppressive activity on T lymphocytes
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DOI：
10.1158/0008-5472.can-06-1819
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发表时间：
2006-09-15
期刊：
影响因子：
11.2
通讯作者：
Rivoltini, Licia
中科院分区：
文献类型：
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作者：
Valenti, Roberta;Huber, Veronica;Rivoltini, Licia
人类肿瘤持续释放内体衍生的微泡，运输多种生物活性分子，对不同的免疫细胞具有潜在的调节作用。在这里，我们报告了第一个证据，表明肿瘤释放的微泡通过损害单核细胞分化为树突状细胞并促进骨髓免疫抑制细胞亚群的生成来改变骨髓细胞功能。从健康供体中分离出的 CD14(+) 单核细胞，在肿瘤来源的微泡存在下，用白细胞介素 (IL)-4 和粒细胞巨噬细胞集落刺激因子分化，转变成 HLA-DR-/low 细胞，保留 CD14 表达，但无法上调共刺激分子，如 CD80 和 CD86。这些表型变化与不同细胞因子的显着释放同时发生，包括 IL-6、肿瘤坏死因子-α 和转化生长因子-β (TGF-β)，以及对激活的 T 细胞增殖和细胞溶解功能的剂量依赖性抑制活性，这种抑制活性可以通过抗 TGF-β 中和抗体逆转。从晚期黑色素瘤患者的血浆中分离出的微泡，而不是从健康供体中分离出来的微泡，对CD14(+)单核细胞介导了类似的作用，使它们向具有TGF-β介导的T细胞功能抑制活性的CD14(+) HLA-DR-/低细胞分化。有趣的是，与健康供体相比，发现黑色素瘤患者外周血中介导 T 淋巴细胞抑制活性的 TGF-β 分泌 CD(14+)HLA-DR 细胞子集显着扩增。这些数据表明，癌症患者体内形成了一种免疫抑制回路，肿瘤通过释放循环微泡来促进抑制性骨髓细胞的产生，而无需细胞与细胞之间的接触。对该途径的关键步骤进行治疗干预可能有助于恢复肿瘤/免疫系统的相互作用，有利于癌症患者中 T 细胞介导的肿瘤生长控制。
Human tumors constitutively release endosome-derived microvesicles, transporting a broad array of biologically active molecules with potential modulatory effects on different immune cells. Here, we report the first evidence that tumor-released microvesicles alter myeloid cell function by impairing monocyte differentiation into dendritic cells and promoting the generation of a myeloid inummosuppressive cell subset. CD14(+) monocytes isolated from healthy donors and differentiated with interleukin (IL)-4 and granulocyte macrophage colony-stimulating factor in the presence of tumor-derived microvesicles turned into HLA-DR-/low cells, retaining CD14 expression and failing to up-regulate costimulatory molecules, such as CD80 and CD86. These phenotypic changes were paralleled by a significant release of different cytokines, including IL-6, tumor necrosis factor-alpha, and transforming growth factor-beta (TGF-beta), and a dosedependent suppressive activity on activated T-cell-proliferation and cytolytic functions, which could be reversed by anti-TGF-beta-neutralizing antibodies. Microvesicles isolated from plasma of advanced melanoma patients, but not from healthy donors, mediated comparable effects on CD14(+) monocytes, skewing their differentiation toward CD14(+) HLA-DR-/low cells with TGF-beta-mediated suppressive activity on T-cell-functions. Interestingly, a subset of TGF-beta-secreting CD(14+)HLA-DRcells mediating suppressive activity on T lymphocytes was found to be significantly expanded in peripheral blood of melanoma patients compared with healthy donors. These data suggest the development in cancer patients of an immunosuppressive circuit by which tumors promote the generation of suppressive myeloid cells through the release of circulating microvesicles and without the need for cell-to-cell contact. Therapeutic interventions on the crucial steps of this pathway may contribute to restore tumor/immune system interactions favoring T-cell-mediated control of tumor growth in cancer patients.