Adoptive T cell transfer therapy (ACT) has emerged as a promising approach to cancer immunotherapy; however, the efficacy of ACT is limited by the T-cell suppressive activity of myeloid-derived suppressor cells (MDSCs), which accumulate in the tumor microenvironment after ACT. We sought to determine whether the efficacy of ACT could be enhanced by co-treatment with docetaxel, a taxane chemotherapy agent that has been shown previously to inhibit MDSC function. Using a mouse tumor model, we demonstrated that ACT and docetaxel synergistically inhibit the growth either of engrafted CT26 colon cancer or 4T1 mammary carcinoma cells. While ACT mediated an increase in the recruitment of MDSCs to the site of the tumor, docetaxel reversed this increase. Furthermore, ex vivo cultures of tumor-associated MDSCs suppressed the cytotoxic activity of tumor-specific T cells, and this suppressive activity was abolished by docetaxel treatment. These results suggest that docetaxel inhibits both the tumor recruitment and T cell suppressive activity of MDSCs. Inhibitors of iNOS and arginase partially inhibited ex vivo MDSC activity, and combined inhibition of iNOS and arginase had a similar effect as docetaxel, which supports the possibility that docetaxel may function by inhibiting ACT-associated activation of these pathways. Furthermore, docetaxel mediated inhibition of the T cell suppressive activity of MDSCs from human blood, which supports the potential clinical applicability of these findings. On the basis of these findings, docetaxel treatment may represent an effective therapeutic approach for reversing immunosuppression by MDSCs subsequent to ACT-based therapy.

中文翻译：

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过继免疫疗法和多西他赛的协同作用抑制了小鼠模型中的肿瘤生长。

过继性T细胞转移疗法（ACT）已成为一种有前景的癌症免疫疗法。但是，ACT的疗效受到髓样来源的抑制细胞（MDSC）的T细胞抑制活性的限制，该细胞在ACT后累积在肿瘤微环境中。我们试图确定通过与多西他赛（紫杉烷化疗药）共同治疗是否可以增强ACT的疗效，多西他赛以前已被证明可以抑制MDSC功能。使用小鼠肿瘤模型，我们证明了ACT和多西他赛协同抑制移植的CT26结肠癌或4T1乳腺癌细胞的生长。尽管ACT介导了MDSCs向肿瘤部位募集的增加，但多西紫杉醇逆转了这种增加。此外，肿瘤相关MDSC的离体培养抑制了肿瘤特异性T细胞的细胞毒活性，多西他赛治疗取消了这种抑制活性。这些结果表明多西他赛同时抑制MDSCs的肿瘤募集和T细胞抑制活性。iNOS和精氨酸酶的抑制剂部分抑制了离体MDSC活性，并且iNOS和精氨酸酶的联合抑制与多西紫杉醇具有相似的作用，这支持了多西紫杉醇可以通过抑制ACT相关的这些途径的激活而发挥作用的可能性。此外，多西紫杉醇介导的对人血MDSCs T细胞抑制活性的抑制作用，支持了这些发现的潜在临床应用性。根据这些发现，