Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity
Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity
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DOI：
10.1182/blood-2007-07-099226
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发表时间：
2008-04-15
期刊：
影响因子：
20.3
通讯作者：
Van Ginderachter, Jo A.
中科院分区：
文献类型：
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作者：
Movahedi, Kiavash;Guilliams, Martin;Van Ginderachter, Jo A.
CD11b(+)Gr-1(+)髓系来源的抑制细胞(MDSCs)的诱导是肿瘤免疫逃避的重要机制。然而，MDSCs的确切性质和功能仍然令人费解，特别是因为它们构成了一个尚未明确界定的异质群体。在这里，我们确定了两个不同的MDSC亚组分，它们在形态、分子和功能上存在明显的差异。这些组分由类似炎性单核细胞的单核细胞(MO-MDSCs)或类似于未成熟中性粒细胞的低密度多形核细胞(PMN-MDSCs)组成。有趣的是，MO-MDSCs和PMN-MDSCs都抑制了抗基因特异性T细胞反应，尽管它们使用了不同的效应分子和信号通路。阻断干扰素-γ或阻断STAT1可部分减弱MO-MDSCs的抑制作用，一氧化氮(NO)是MO-MDSCs的介质之一。相反，尽管PMN-MDSCs的抑制功能严格需要干扰素-γ，但这并不依赖于STAT1信号或NO的产生。最后，MO-MDSCs是高度抗增殖、产生NO的成熟巨噬细胞的潜在前体细胞。然而，不同的肿瘤不同地调节这种固有的MO-MDSC分化程序，表明这种现象是由肿瘤驱动的。总体而言，我们的数据通过揭示机制上不同的MDSC亚群来优化肿瘤诱导的MDSC功能，这可能与MDSC靶向治疗相关。
The induction of CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs) is an important immune-evading mechanism used by tumors. However, the exact nature and function of MDSCs remain elusive, especially because they constitute a heterogeneous population that has not yet been clearly defined. Here, we identified 2 distinct MDSC subfractions with clear morphologic, molecular, and functional differences. These fractions consisted of either mononuclear cells (MO-MDSCs), resembling inflammatory monocytes, or low-density polymorphonuclear cells (PMN-MDSCs), akin to immature neutrophils. Interestingly, both MO-MDSCs and PMN-MDSCs suppressed anti gen-specific T-cell responses, albeit using distinct effector molecules and signaling pathways. Blocking IFN-gamma or disrupting STAT1 partially impaired suppression by MO-MDSCs, for which nitric oxide (NO) was one of the mediators. In contrast, while IFN-gamma was strictly required for the suppressor function of PMN-MDSCs, this did not rely on STAT1 signaling or NO production. Finally, MO-MDSCs were shown to be potential precursors of highly antiproliferative NO-producing mature macrophages. However, distinct tumors differentially regulated this inherent MO-MDSC differentiation program, indicating that this phenomenon was tumor driven. Overall, our data refine tumor-induced MDSC functions by uncovering mechanistically distinct MDSC subpopulations, potentially relevant for MDSC-targeted therapies.