PT  - JOURNAL ARTICLE
AU  - Luo, Fan
AU  - Luo, Min
AU  - Rong, Qi-Xiang
AU  - Zhang, Hong
AU  - Chen, Zhen
AU  - Wang, Fang
AU  - Zhao, Hong-Yun
AU  - Fu, Li-Wu
TI  - Niclosamide, an antihelmintic drug, enhances efficacy of PD-1/PD-L1 immune checkpoint blockade in non-small cell lung cancer
AID  - 10.1186/s40425-019-0733-7
DP  - 2019 Dec 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - 245
VI  - 7
IP  - 1
4099  - http://jitc.bmj.com/content/7/1/245.short
4100  - http://jitc.bmj.com/content/7/1/245.full
SO  - J Immunother Cancer2019 Dec 01; 7
AB  - Background PD-1/PD-L1 blockade has received approval for clinical application due to its encouraging benefit with improving prognosis in selected populations. Unfortunately, the response to immunotherapy for many patients remains unsatisfactory. It remains a great challenge to generate potential combinations that will outperform single agents alone with regard to anti-tumor activity.Methods Using NSCLC cell lines and mouse models, we explored the effects of combined niclosamide and PD-L1 blockade on tumor growth and T cell function. Furthermore, we investigated the relationship between PD-L1 and p-STAT3 expression in tumor samples from patients with NSCLC using IHC, as well as their relationship to patient survival.Results In vitro, niclosamide, an antihelmintic drug, enhanced the cancer cell lysis mediated by T cells in the presence of PD-L1 blockade. Accordingly, mice treated with niclosamide and PD-L1 antibody showed significant delay in tumor growth and increased survival which were associated with the increase of tumor infiltrating T cells and granzyme B release. Importantly, we found niclosamide could decrease the expression of PD-L1 in both a concentration- and time-dependent manner in NSCLC cells, which was linked to the blockage of p-STAT3 binding to the promoter of PD-L1.Conclusions An enhancement of PD-L1 antibody by niclosamide was observed in inhibition of NSCLC growth in vitro and in vivo, which was involved in blockage of p-STAT3 binding to promoter of PD-L1 and finally downregulation of PD-L1 expression. These encourage the combination therapy of niclosamide and PD-1/PD-L1 blockade to be further studied in clinic.Fan Luo and Min Luo contributed equally to this work.Abbreviations:CTLA-4cytotoxic T lymphocyte antigen 4LLCcellLewis lung cancer cellNSCLCnon-small cell lung cancerPBMCsperipheral blood mononuclear cellsPD-1programmed cell death protein 1PD-L1Programmed cell death 1 ligandPFSProgression-free survivalSTAT3signal transducer and activator of transcription 3TMBTumor mutation burdenTNF-αtumor necrosis factor-α