Mitomycin C synergizes with PD-L1 blockade in treatment of non-small cell lung cancer

被引：0

作者：

LUO Min ^{[1
]}

ZHANG Hong ^{[1
]}

WU Shao-cong ^{[1
]}

CHEN Zhen ^{[1
]}

LIANG Shao-bo ^{[1
]}

WANG Fang ^{[1
]}

FU Li-wu ^{[1
]}

机构：

[1] State Key Laboratory of Oncology in South China, Col aborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-Sen University Cancer Center

来源：

中国药理学与毒理学杂志 | 2019年 / 10期

关键词：

mitomycin C; PD-L1; immunotherapy; MHC-I; c-Jun; P65;

D O I：

暂无

中图分类号：

R734.2 [肺肿瘤];

学科分类号：

100214 ;

摘要：

OBJECTIVE Programmed death 1 ligand(PD-L1) checkpoint inhibitor was a promising therapy but the response rate was only about 20%. Chemotherapy was reported to final y kil tumor cel s by triggering immune response. To improve the response of PD-L1 blockade,we tried to find chemotherapeuticaldrugs to combine with PD-L1 antibody(Ab). METHODS Non-small cell lung cancer(NSCLC) cells were pre-treated with mitomycin C(MMC) and then co-cultured with PBMCs to explore the effect of the combination of MMC with PD-L1 Ab. Lewis lung cancer(LLC) cells were used to establish xenograft model in mice and subjected to MMC or PD-L1 Ab treatment alone or combo. RESULTS MMC increased the expressions of PD-L1 and MHC-Ⅰ in NSCLC cells in vitro and in vivo and enhanced the activity of lymphocytes against NSCLC in vitro.The mice treated with combo of PD-L1 Ab with MMC showed an improved overall survival and inhibition of the tumor growth compared to monotherapy,which was linked to the increases of lymphocyte infiltration and granzyme B release in LLC cell xenograftmodels in mice. Mechanically, MMC activated the ERK pathwayand subsequently activated c-Jun that bound with PD-L1 promoter and recruited its co-factor STAT3 to enhance PD-L1 expression. Meanwhile, the ERK pathway activated P65 to promote the MHC-I expression. CONCLUSION A combination of MMC with PD-L1 blockade may improve the antitumor response and offer a promising new treatment modality against NSCLC and encourage to further study to confirm in clinic.

引用

页码：885 / 885

页数：1