Cancer-cell-secreted CXCL11 promoted CD8+ T cells infiltration through docetaxel-induced-release of HMGB1 in NSCLC
Cancer-cell-secreted CXCL11 promoted CD8+ T cells infiltration through docetaxel-induced-release of HMGB1 in NSCLC
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DOI：
10.1186/s40425-019-0511-6
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发表时间：
2019-02-11
影响因子：
10.9
通讯作者：
Zhang, Yi
中科院分区：
文献类型：
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作者：
Gao, Qun;Wang, Shumin;Zhang, Yi
化疗联合免疫治疗成为肺癌干预的主要趋势；然而，化疗如何促进免疫功能仍然是一个谜。因此，我们试图确定化疗如何促进免疫功能。方法采用实时定量逆转录pcr技术检测100例非小细胞肺癌患者CD8、功能标志物（IFN-、颗粒酶B、穿孔素）及特异性趋化因子的表达。通过功能实验观察化疗药物多西他赛（docetaxel， DOC）是否能改变HMGB1和CXCL11的表达，影响CD8(+) T细胞对肿瘤微环境的浸润特性。采用流式细胞术、免疫荧光和western blotting检测HMGB1和CXCL11的释放机制。在体内实验中，我们证实了DOC如何增强HER2-CAR - T细胞向肿瘤部位的募集。结果我们发现，DOC上调肿瘤微环境中趋化因子受体配体CXCL11的表达，从而增强CD8(+) T细胞募集。DOC处理显著增加HMGB1的释放，并呈ros依赖性。重组蛋白HMGB1在体外通过NF-B激活刺激CXCL11的分泌。与对照组相比，doc处理小鼠的肿瘤表现出更高的HMGB1和CXCL11表达，更多的HER2-CAR - T细胞浸润，并且进展减缓。HMGB1、CXCL11表达升高与肺癌患者总生存期延长呈正相关。结论DOC通过增强HMGB1和CXCL11的分泌，诱导CD8(+) T细胞向肿瘤微环境募集，从而提高抗肿瘤效果，提示调节HMGB1-CXCL11轴可能有助于治疗非小细胞肺癌。
BackgroundChemotherapy combined with immunotherapy becomes the main trend in lung cancer intervention; however, how chemotherapy promotes the immune function remains elusive. Therefore, we sought to determine how chemotherapy promotes the immune function.MethodsWe determined in 100 NSCLC patients the expression of CD8, functional markers (IFN-, Granzyme B, and Perforin) and specific chemokines by quantitative real-time reverse transcriptase-PCR. Functional experiments were carried out to check whether docetaxel (DOC), a chemotherapeutic agent, modifies the expression of HMGB1 and CXCL11, and influences the infiltration properties of CD8(+) T cells to the tumor microenvironment. The mechanism of the release of HMGB1 and CXCL11 was determined by flow cytometry, immunofluorescence and western blotting. In in vivo experiment, we confirmed how DOC enhanced the recruitment of HER2-CAR T cells to tumor sites.ResultsWe found that DOC upregulated the expression of chemokine receptor ligand CXCL11 in tumor microenvironment and subsequently enhanced CD8(+) T cell recruitment. DOC treatment significantly increased HMGB1 release in an ROS-dependent manner. Recombinant protein HMGB1 stimulated the secretion of CXCL11 via NF-B activation in vitro. Tumors from DOC-treated mice exhibited higher expression of HMGB1 and CXCL11, more HER2-CAR T cell infiltration, and reduced progression, relative to control. Increased HMGB1 and CXCL11 expressions were positively correlated with prolonged overall survival of lung cancer patients.ConclusionsOur results demonstrate that DOC induces CD8(+) T cell recruitment to the tumor microenvironment by enhancing the secretion of HMGB1 and CXCL11, thus improving the anti-tumor efficacy, indicating that modulating the HMGB1-CXCL11 axis might be helpful for NSCLC treatment.