Antitumor effect of paclitaxel is mediated by inhibition of myeloid-derived suppressor cells and chronic inflammation in the spontaneous melanoma model.
Antitumor effect of paclitaxel is mediated by inhibition of myeloid-derived suppressor cells and chronic inflammation in the spontaneous melanoma model.
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紫杉醇的抗肿瘤作用是通过抑制髓样衍生的抑制细胞和自发黑色素瘤模型中的慢性炎症来介导的。
DOI：
10.4049/jimmunol.1202781
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发表时间：
2013-03-01
期刊：
影响因子：
--
通讯作者：
Umansky V
中科院分区：
文献类型：
--
作者：
Sevko A;Michels T;Vrohlings M;Umansky L;Beckhove P;Kato M;Shurin GV;Shurin MR;Umansky V
紫杉醇的抗肿瘤作用通常归因于抑制微管动力学，导致细胞分裂缺陷。新数据表明，在超低非细胞毒性浓度下，紫杉醇在体外调节免疫细胞中小 Rho GTP 酶的活性，小 Rho GTP 酶是细胞内肌动蛋白动力学的关键调节因子。然而，紫杉醇的体内免疫调节特性尚未得到评估。我们使用模拟人皮肤黑色素瘤的 ret 转基因小鼠黑色素瘤模型，测试了超低非细胞毒性剂量紫杉醇对体内肿瘤微环境中骨髓源性抑制细胞 (MDSC)、慢性炎症介质和 T 细胞活性的影响。紫杉醇的施用显着降低了肿瘤浸润性 MDSC 的积累和免疫抑制活性，而不改变骨髓造血功能。这与 MDSC 中 p38 MAPK 活性、TNF-α 和产生以及 S100A9 表达的抑制有关。肿瘤环境中慢性炎症介质的产生也减少了。重要的是，紫杉醇应用后肿瘤负荷的减少和动物存活率的增加是由 CD8 T 细胞效应功能的恢复介导的。我们认为，非细胞毒性剂量的紫杉醇在体内阻断 MDSC 免疫抑制潜力的能力代表了一种新的治疗策略，可以下调肿瘤微环境中的免疫抑制和慢性炎症，从而增强伴随抗癌治疗的疗效。
The anti-tumor effects of paclitaxel are generally attributed to the suppression of microtubule dynamics resulting in defects in cell division. New data demonstrated that in ultra-low non-cytotoxic concentrations, paclitaxel modulated in immune cells in vitro the activity of small Rho GTPases, the key regulators of intracellular actin dynamics. However, the immunomodulatory properties of paclitaxel in vivo have not been evaluated. Using here the ret transgenic murine melanoma model, which mimics human cutaneous melanoma, we tested effects of ultra-low non-cytotoxic dose paclitaxel on functions of myeloid-derived suppressor cells (MDSCs), chronic inflammatory mediators, and T cell activities in the tumor microenvironment in vivo. Administration of paclitaxel significantly decreased accumulation and immunosuppressive activities of tumor-infiltrating MDSCs without alterations of the bone marrow hematopoiesis. This was associated with the inhibition of p38 MAPK activity, TNF-α and production and S100A9 expression in MDSCs. The production of mediators of chronic inflammation in the tumor milieu was also diminished. Importantly, reduced tumor burden and increased animal survival upon paclitaxel application was mediated by the restoration of CD8 T cell effector functions. We suggest that the ability of paclitaxel in non-cytotoxic dose to block the immunosuppressive potential of MDSCs in vivo represents a new therapeutic strategy to down-regulate immunosuppression and chronic inflammation in the tumor microenvironment for enhancing the efficacy of concomitant anti-cancer therapies.
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单核细胞CCR2（+）髓样衍生的抑制细胞通过将活化的CD8 T细胞浸润限制在肿瘤微环境中，从而促进免疫逃逸。
影响因子：
11.2
作者：
Lesokhin AM;Hohl TM;Kitano S;Cortez C;Hirschhorn-Cymerman D;Avogadri F;Rizzuto GA;Lazarus JJ;Pamer EG;Houghton AN;Merghoub T;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
7.3
作者：
Ho, FM;Lai, CC;Lin, WW
通讯作者：
Lin, WW
影响因子：
11.5
作者：
Gajewski, Thomas F.
通讯作者：
Gajewski, Thomas F.
影响因子：
6.4
作者：
Chen, BC;Chen, YH;Lin, WW
通讯作者：
Lin, WW
影响因子：
3.3
作者：
Sevko, Alexandra;Kremer, Veronika;Umansky, Viktor
通讯作者：
Umansky, Viktor