Deregulation of Apoptotic Factors Bcl-xL and Bax Confers Apoptotic Resistance to Myeloid-derived Suppressor Cells and Contributes to Their Persistence in Cancer
Deregulation of Apoptotic Factors Bcl-xL and Bax Confers Apoptotic Resistance to Myeloid-derived Suppressor Cells and Contributes to Their Persistence in Cancer
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DOI：
10.1074/jbc.m112.434530
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发表时间：
2013-06-28
影响因子：
4.8
通讯作者：
Liu, Kebin
中科院分区：
文献类型：
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作者：
Hu, Xiaolin;Bardhan, Kankana;Liu, Kebin
髓系来源的抑制细胞(MDSCs)是一种异质的未成熟髓系细胞，随着肿瘤的进展而积聚。来自小鼠模型和人类癌症患者的令人信服的数据表明，肿瘤诱导的炎症介质诱导MDSC分化。然而，MDSC持久性背后的机制在很大程度上是未知的。在这里，我们证明了与来自无肿瘤小鼠的相同表型的髓系细胞相比，肿瘤诱导的MDSCs的自发凋亡率显著减少。在肿瘤诱导的MDSCs中，细胞表面Fas受体显著降低，与细胞凋亡率的减少相一致。对Fas受体下游关键凋亡介质的筛选显示，在肿瘤诱导的MDSCs中，IRF8和Bax的表达水平降低，而Bclxl的表达增加。我们进一步证实，在体内原代培养的髓系细胞中，IRF8直接与Bax和Bclx启动子结合，IRF8缺陷的MDSC样细胞也表现出Bclxl增加和Bax表达降低。对CD69和CD25水平的分析表明，在荷瘤宿主中，细胞毒性T淋巴细胞(CTL)被部分激活。值得注意的是，在荷瘤宿主的CTL中有选择性地激活FasL，而不是穿孔素和颗粒酶。ABT-737可显著提高MDSCs对Fas诱导的细胞凋亡的敏感性。更重要的是，ABT-737治疗增加了荷瘤小鼠MDSC的自发凋亡率，减少了MDSC的积聚。因此，我们的数据确定MDSCs通过下调IRF8来改变Bax和Bclxl的表达，从而解除对Fas介导的凋亡途径的调控，从而逃避宿主CTL的清除。因此，靶向Bcl-xL在抑制MDSC在肿瘤治疗中的持久性方面具有潜在的有效作用。
Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells that accumulate in response to tumor progression. Compelling data from mouse models and human cancer patients showed that tumor-induced inflammatory mediators induce MDSC differentiation. However, the mechanisms underlying MDSC persistence is largely unknown. Here, we demonstrated that tumor-induced MDSCs exhibit significantly decreased spontaneous apoptosis as compared with myeloid cells with the same phenotypes from tumor-free mice. Consistent with the decreased apoptosis, cell surface Fas receptor decreased significantly in tumor-induced MDSCs. Screening for changes of key apoptosis mediators downstream the Fas receptor revealed that expression levels of IRF8 and Bax are diminished, whereas expression of Bcl-xL is increased in tumor-induced MDSCs. We further determined that IRF8 binds directly to Bax and Bcl-x promoter in primary myeloid cells in vivo, and IRF8-deficient MDSC-like cells also exhibit increased Bcl-xL and decreased Bax expression. Analysis of CD69 and CD25 levels revealed that cytotoxic T lymphocytes (CTLs) are partially activated in tumor-bearing hosts. Strikingly, FasL but not perforin and granzymes were selectively activated in CTLs in the tumor-bearing host. ABT-737 significantly increased the sensitivity of MDSCs to Fas-mediated apoptosis in vitro. More importantly, ABT-737 therapy increased MDSC spontaneous apoptosis and decreased MDSC accumulation in tumor-bearing mice. Our data thus determined that MDSCs use down-regulation of IRF8 to alter Bax and Bcl-xL expression to deregulate the Fas-mediated apoptosis pathway to evade elimination by host CTLs. Therefore, targeting Bcl-xL is potentially effective in suppression of MDSC persistence in cancer therapy.