Mitomycin C enhanced the efficacy of PD-L1 blockade in non-small cell lung cancer

Min Luo,Kenneth K W To,Hong Zhang,Zhen Chen,Shaocong Wu,Fang Wang,Shaobo Liang,Liwu Fu

doi:10.1038/s41392-020-0200-4

Abstract

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.

Highlights

INTRODUCTION Human body makes use ofT cells to selectively recognize and kill external pathogens and unhealthy cells, including cancer cells, by coordinating innate and adaptive immune responses
programmed death ligand 1 (PD-L1) expression was upregulated by MMC in concentration- and time-dependent manners The effect of several conventional chemotherapeutical drugs at non-cytotoxic concentration on PD-L1 expression in three non-small cell lung cancer (NSCLC) cells (A549, H1299, and H460) was evaluated after 48-h treatment (Fig. 1a)
MMC potentiated the anticancer efficacy of PD-L1 blockade in NSCLC in vivo To determine whether upregulation of PD-L1 by MMC would affect the antitumor immune activity, H460 cells were pretreated with MMC for 24 h, and co-cultured with peripheral blood mononuclear cells (PBMCs) for another 24 h

Summary

Introduction

INTRODUCTION Human body makes use ofT cells to selectively recognize and kill external pathogens and unhealthy cells, including cancer cells, by coordinating innate and adaptive immune responses. The programmed cell death-1 (PD-1) receptor is a key inhibitory immune checkpoint protein expressing on the surface of activated T cells. Its ligand programmed death ligand 1 (PD-L1), known as B7-H11 is commonly expressed in many cell types, including T cells, B cells, monocytes, antigen process cells (APCs), and epithelial cells.[2,3] The PD-1/PD-L1 interaction limits the development of T cells response, thereby ensuring the activation of immune system appropriately.[2,3] Cancer cells can exploit various immune checkpoints to evade immune detection and elimination. While durable tumor regression could be achieved in some patients, only

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