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首页> 外文期刊>Cancer immunology, immunotherapy : >Paclitaxel reduces regulatory T cell numbers and inhibitory function and enhances the anti-tumor effects of the TLR9 agonist PF-3512676 in the mouse
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Paclitaxel reduces regulatory T cell numbers and inhibitory function and enhances the anti-tumor effects of the TLR9 agonist PF-3512676 in the mouse

机译：紫杉醇减少小鼠的调节性T细胞数量和抑制功能，并增强TLR9激动剂PF-3512676在小鼠中的抗肿瘤作用

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摘要

The anti-tumor properties of Toll-like receptor (TLR) 9 agonist CpG oligodeoxynucleotides (ODN) are enhanced by combinations with several cytotoxic chemotherapy regimens. The mechanisms of this added benefit, however, remain unclear. We now report that, similar to the depletion of regulatory T cells (Treg) using anti-CD25, paclitaxel increased the anti-tumor effect of the TLR9 agonist PF-3512676 in a CD8 + T cell-dependent fashion. Paclitaxel treatment decreased Treg numbers in a TLR4-independent fashion, and preferentially affected cycling Treg expressing high levels of FoxP3. The paclitaxel-induced reduction in Treg FoxP3 expression was associated with reduced inhibitory function. Adoptively transferred tumor-antigen specific CD8 + T cells proliferated better in mice treated with paclitaxel and their recruitment in the tumor was increased. However, the systemic frequency of PF-3512676-induced tumor-antigen specific effector CD8 + T cells decreased with paclitaxel, suggesting opposite effects of paclitaxel on the anti-tumor response. Finally, gene expression profiling and studies of tumor-associated immune cells revealed a complex modulation of the PF-3512676-induced immune response by paclitaxel, including a decrease of IL-10 expression and an increase in IL-17-secreting CD4 + T cells. Collectively, these data suggest that paclitaxel combined with PF-3512676 may not only promote a better anti-tumor CD8 + response though increased recruitment in the tumor, possibly through Treg depletion and suppression, but also exerts more complex immune modulatory effects.
机译：通过与几种细胞毒性化学疗法联合使用，可增强Toll样受体（TLR）9激动剂CpG寡脱氧核苷酸（ODN）的抗肿瘤特性。但是，这种增加的利益的机制仍不清楚。我们现在报道，紫杉醇类似于使用抗CD25的调节性T细胞（Treg）耗竭，以CD8 ​​+ T细胞依赖性方式增加了TLR9激动剂PF-3512676的抗肿瘤作用。紫杉醇治疗以TLR4独立的方式降低Treg数量，并优先影响表达高水平FoxP3的自行车Treg。紫杉醇诱导的Treg FoxP3表达降低与抑制功能降低有关。过继转移的肿瘤抗原特异性CD8 + T细胞在用紫杉醇治疗的小鼠中增殖更好，并且在肿瘤中的募集增加。然而，紫杉醇可降低PF-3512676诱导的肿瘤抗原特异性效应CD8 + T细胞的全身频率，提示紫杉醇对抗肿瘤反应的作用相反。最后，基因表达谱分析和与肿瘤相关的免疫细胞的研究表明，紫杉醇对PF-3512676诱导的免疫反应具有复杂的调节作用，包括IL-10表达减少和IL-17分泌CD4 + T细胞增加。 。总体而言，这些数据表明，紫杉醇联合PF-3512676不仅可能通过增加Treg的消耗和抑制而增加了在肿瘤中的募集，而且还促进了更好的抗肿瘤CD8 +反应，而且还发挥了更为复杂的免疫调节作用。

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