Synergistic effect of adoptive immunotherapy and docetaxel inhibits tumor growth in a mouse model
Synergistic effect of adoptive immunotherapy and docetaxel inhibits tumor growth in a mouse model
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过继免疫疗法和多西紫杉醇的协同作用抑制小鼠模型中的肿瘤生长
DOI：
10.1016/j.cellimm.2019.104036
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发表时间：
2020-02-01
影响因子：
4.3
通讯作者：
Lu, Xu
中科院分区：
文献类型：
--
作者：
Hu, Yuefeng;Liu, Jingwei;Lu, Xu
过继性T细胞转移疗法（ACT）已成为一种有前景的癌症免疫治疗方法；然而，ACT的疗效受到髓源性抑制细胞（MDSCs）的T细胞抑制活性的限制，这些细胞在ACT后会在肿瘤微环境中积聚。我们试图确定，与多西他赛（一种此前已被证明可抑制MDSC功能的紫杉烷类化疗药物）联合治疗是否能提高ACT的疗效。通过使用小鼠肿瘤模型，我们证明了ACT和多西他赛协同抑制移植的CT26结肠癌细胞或4T1乳腺癌细胞的生长。虽然ACT介导了MDSCs向肿瘤部位募集的增加，但多西他赛逆转了这种增加。此外，肿瘤相关MDSCs的体外培养会抑制肿瘤特异性T细胞的细胞毒性活性，而多西他赛处理可消除这种抑制活性。这些结果表明，多西他赛既抑制MDSCs向肿瘤的募集，又抑制其T细胞抑制活性。诱导型一氧化氮合酶（iNOS）和精氨酸酶的抑制剂部分抑制了体外MDSC的活性，同时抑制iNOS和精氨酸酶的效果与多西他赛类似，这表明多西他赛可能通过抑制与ACT相关的这些通路的激活来发挥作用。此外，多西他赛可抑制人血液中MDSCs的T细胞抑制活性，这支持了这些研究结果具有潜在临床应用价值的可能性。基于这些发现，多西他赛治疗可能是一种有效的治疗方法，用于逆转基于ACT治疗后MDSCs介导的免疫抑制。
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 tumorspecific 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.