Abstract
BackgroundPD-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.MethodsUsing 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.ResultsIn 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.ConclusionsAn 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.
Highlights
Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality and has poor prognosis [1]
To investigate whether niclosamide combined with programmed cell death 1 (PD-1)/programmed cell death 1 ligand (PD-L1) blockade can exert a synergistic immunotherapeutic effect, we tested the efficacy of the combined use of niclosamide and anti-PD-L1 blocking antibodies in vitro
Niclosamide combined with PD-L1 antibody showed significantly higher tumor growth inhibition compared to niclosamide alone or PD-L1 blockade alone (Fig. 1be)
Summary
Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality and has poor prognosis [1]. Some clinical trials about combining anti-PD-1/PD-L1 with anti-CTLA-4 have obtained positive results in various cancers, including melanoma [6] and NSCLC [7]. The promising therapeutic effects of the aforementioned combination therapy have been proved in some phase I or II clinical studies, the phase III MYSTIC trial has not observed positive results in the treatment of NSCLC patients [8]. Elevated indoleamine 2, 3-dioxygenase(IDO) is positively correlated with increased tumor grade, peripheral immune tolerance and poor prognosis in various cancers [9]. Despite previous encouraging response of the IDO inhibitors in combination with anti-PD-1 in many different solid tumors was observed in preclinical investigations and early-phase clinical studies, a phase III clinical trial demonstrated negative results with regard to such a combination treating metastatic melanoma [10]. It remains a great challenge to generate potential combinations that will outperform single agents alone with regard to anti-tumor activity
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