Mitomycin C enhanced the efficacy of PD-L1 blockade in non-small cell lung cancer
Mitomycin C enhanced the efficacy of PD-L1 blockade in non-small cell lung cancer
复制标题
丝裂霉素 C 增强 PD-L1 阻断对非小细胞肺癌的疗效
DOI：
10.1038/s41392-020-0200-4
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发表时间：
2020-08-28
影响因子：
39.3
通讯作者：
Fu, Liwu
中科院分区：
文献类型：
--
作者：
Luo, Min;Wang, Fang;Fu, Liwu
程序性死亡配体1（PD-L1）免疫检查点抑制剂是治疗癌症的有前途的治疗药物，但缓解率<20%。一些化疗药物除了具有直接的细胞毒性外，还可以激活抗癌免疫反应，杀死癌细胞。我们的研究探讨了化疗药物与PD-L1抗体的组合，以提高PD-L1阻断的响应率。用丝裂霉素C（MMC）预处理非小细胞肺癌（NSCLC）细胞，然后与外周血单个核细胞（PBMCs）共培养，观察MMC联合PD-L1抗体的作用。还在携带刘易斯肺癌（LLC）细胞的C57 BL/6小鼠中体内评价了药物组合。MMC在体内外均能增加NSCLC细胞PD-L1和MHC-I的表达，增强淋巴细胞对NSCLC的体外杀伤作用。在LLC荷瘤小鼠模型中，发现MMC和PD-L1抗体的组合在延缓肿瘤生长和延长总生存期方面比任一单独治疗更有效，这与淋巴细胞浸润和颗粒酶B释放增加相关。从机制上讲，MMC激活了ERK通路，随后增强了c-JUN与PD-L1启动子的结合，并招募了其辅因子STAT 3以增加PD-L1表达。上调的ERK途径显示激活p65以增加MHC-I表达。MMC显示出增强NSCLC细胞中PD-L1阻断的功效。进一步的研究是必要的，以将这些发现转化为临床应用。
Programmed death ligand 1 (PD-L1) immune checkpoint inhibitors are promising therapeutic agents for treating cancers but the response rate is <20%. Some chemotherapeutic drugs could also activate an anticancer immune response to kill cancer cells, apart from their direct cytotoxicity. Our study investigated the combination of chemotherapeutic drugs with PD-L1 antibody to enhance the response rate of PD-L1 blockade. Non-small cell lung cancer (NSCLC) cells were pre-treated with mitomycin C (MMC) and then co-cultured with peripheral blood mononuclear cells (PBMCs) to investigate the effect of the combination of MMC with PD-L1 antibody. The drug combination was also evaluated in vivo in Lewis lung cancer (LLC) cells-bearing C57BL/6 mice. MMC increased the expressions of PD-L1 and MHC-I in NSCLC cells in vitro and in vivo and enhanced the cytotoxic effect of lymphocytes on NSCLC in vitro. In LLC-bearing mouse model, the combination of MMC and PD-L1 antibody was found to be more effective in retarding tumor growth and prolonging overall survival than either single treatment alone, which was associated with increased lymphocyte infiltration and granzyme B release. Mechanistically, MMC activated the ERK pathway, which subsequently enhanced the binding of c-JUN to the PD-L1 promoter and recruited its co-factor STAT3 to increase PD-L1 expression. The upregulated ERK pathway was shown to activate p65 to increase the MHC-I expression. MMC was shown to enhance the efficacy of PD-L1 blockade in NSCLC cells. Further study is warranted to translate the findings to clinical application.