Hydroxychloroquine induced lung cancer suppression by enhancing chemo-sensitization and promoting the transition of M2-TAMs to M1-like macrophages.
Hydroxychloroquine induced lung cancer suppression by enhancing chemo-sensitization and promoting the transition of M2-TAMs to M1-like macrophages.
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羟氯喹通过增强化疗敏化和促进 M2-TAM 向 M1 样巨噬细胞的转变来诱导肺癌抑制。
DOI：
10.1186/s13046-018-0938-5
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发表时间：
2018-10-29
期刊：
影响因子：
--
通讯作者：
Yu X
中科院分区：
文献类型：
--
作者：
Li Y;Cao F;Li M;Li P;Yu Y;Xiang L;Xu T;Lei J;Tai YY;Zhu J;Yang B;Jiang Y;Zhang X;Duo L;Chen P;Yu X
溶酶体相关药物被认为可能是癌症化疗的化学增敏剂和免疫调节剂。我们探讨了羟基氯喹(HCQ)联合化疗在肺癌治疗中的潜在作用和机制。采用细胞存活率测定和动物模型研究了联合治疗对非小细胞肺癌的影响。用溶酶体传感器和共聚焦显微镜观察HCQ对溶酶体pH的影响。用流式细胞仪分析HCQ对肿瘤免疫微环境的影响。盐酸奎宁可提高癌细胞溶酶体的pH值，使P-gp失活，同时增加药物从溶酶体释放到细胞核内。此外，单一HCQ疗法通过诱导巨噬细胞调节的抗肿瘤CD8+T细胞免疫来抑制肺癌。此外，HCQ还可促进M2类肿瘤相关巨噬细胞(TAMs)向类M1巨噬细胞的转化，导致CD8+T细胞向肿瘤微环境的渗透。HCQ通过逆转药物在溶酶体内的滞留，增强CD8+T细胞免疫应答，发挥抗NSCLC细胞的作用。提示HCQ可作为肺癌化疗的化疗增敏剂和免疫调节剂应用于临床。本文的在线版本(10.1186/s13046-0180938-5)包含补充材料，可供授权用户使用。
Lysosome-associated agents have been implicated as possible chemo-sensitizers and immune regulators for cancer chemotherapy. We investigated the potential roles and mechanisms of hydroxychloroquine (HCQ) in combination with chemotherapy in lung cancer treatment. The effects of combined treatment on non-small cell lung cancer (NSCLC) were investigated using cell viability assays and animal models. The influence of HCQ on lysosomal pH was evaluated by lysosomal sensors and confocal microscopy. The effects of HCQ on the tumour immune microenvironment were analysed by flow cytometry. HCQ elevates the lysosomal pH of cancer cells to inactivate P-gp while increasing drug release from the lysosome into the nucleus. Furthermore, single HCQ therapy inhibits lung cancer by inducing macrophage-modulated anti-tumour CD8+ T cell immunity. Moreover, HCQ could promote the transition of M2 tumour-associated macrophages (TAMs) into M1-like macrophages, leading to CD8+ T cell infiltration into the tumour microenvironment. HCQ exerts anti-NSCLC cells effects by reversing the drug sequestration in lysosomes and enhancing the CD8+ T cell immune response. These findings suggest that HCQ could act as a promising chemo-sensitizer and immune regulator for lung cancer chemotherapy in the clinic. The online version of this article (10.1186/s13046-018-0938-5) contains supplementary material, which is available to authorized users.
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