A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers.
A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers.
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DOI：
10.1158/1078-0432.ccr-10-0733
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发表时间：
2010-09-15
期刊：
影响因子：
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通讯作者：
Djeu JY
中科院分区：
文献类型：
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作者：
Kodumudi KN;Woan K;Gilvary DL;Sahakian E;Wei S;Djeu JY
骨髓源性抑制细胞（MDSC）在荷瘤宿主中积累，并与免疫抑制有关。迄今为止，只有少数研究评估化疗药物对MDSC的直接影响。抑制MDSC的药剂可用于治疗患有各种癌症的患者。我们研究了多西他赛对4 T1-Neu乳腺肿瘤荷瘤小鼠免疫功能的体内影响，以检查是否具有良好的免疫调节作用伴肿瘤抑制。主要关注MDSC的分化状态及其调节T细胞应答的能力。多西他赛给药显著抑制了4 T1-Neu荷瘤小鼠的肿瘤生长，并显著降低了脾脏中MDSC的比例。治疗还选择性地增加CTL应答。多西他赛预处理的MDSC与OT-II脾细胞在存在OVA 323 -339的情况下共培养，在体外显示OT-II特异性CD 4活化和扩增。在表征MDSC的M1（CCR 7）和M2 [甘露糖受体（CD 206）]标记物的表型时，来自未治疗的肿瘤携带者的MDSC主要为MR+，具有很少的CCR 7+细胞。多西他赛治疗使MDSC向M1样表型极化，导致40%的MDSC在体内和体外表达CCR 7，并且巨噬细胞分化标志物如MHC II类、CD 11 c和CD 86上调。有趣的是，多西他赛在MR+ MDSC中选择性诱导细胞死亡，而保留M1样表型。最后，信号转导和转录激活因子3的抑制可能是部分负责观察到的结果。这些结果表明，在目前的免疫方案中加入多西他赛具有潜在的临床获益。
Myeloid-derived suppressor cells (MDSC) accumulate in tumor-bearing hosts and are associated with immune suppression. To date, there have only been few studies that evaluate the direct effect of chemotherapeutic agents on MDSCs. Agents that inhibit MDSCs may be useful in the treatment of patients with various cancers. We investigated the in vivo effects of docetaxel on immune function in 4T1-Neu mammary tumor-bearing mice to examine if a favorable immunomodulatory effect accompanies tumor suppression. Primary focus was on the differentiation status of MDSCs and their ability to modulate T-cell responses. Docetaxel administration significantly inhibited tumor growth in 4T1-Neu tumor-bearing mice and considerably decreased MDSC proportion in the spleen. The treatment also selectively increased CTL responses. Docetaxel-pretreated MDSCs cocultured with OT-II splenocytes in the presence of OVA323–339 showed OT-II–specific CD4 activation and expansion in vitro. In characterizing the phenotype of MDSCs for M1 (CCR7) and M2 [mannose receptor (CD206)] markers, MDSCs from untreated tumor bearers were primarily MR+ with few CCR7+ cells. Docetaxel treatment polarized MDSCs toward an M1-like phenotype, resulting in 40% of MDSCs expressing CCR7 in vivo and in vitro, and macrophage differentiation markers such as MHC class II, CD11c, and CD86 were upregulated. Interestingly, docetaxel induced cell death selectively in MR+ MDSCs while sparing the M1-like phenotype. Finally, inhibition of signal transducer and activator of transcription 3 may in part be responsible for the observed results. These findings suggest potential clinical benefit for the addition of docetaxel to current immunotherapeutic protocols.