Ze-Qi-Tang Formula Induces Granulocytic Myeloid-Derived Suppressor Cell Apoptosis via STAT3/S100A9/Bcl-2/Caspase-3 Signaling to Prolong the Survival of Mice with Orthotopic Lung Cancer.

Zi-Hang Xu,Yang-Zhuangzhuang Zhu,Wan-Tao Wang,Yi-Fei Hou,Jie Wang,Fei Zhang,Shi-Guo Zhu,Xue-Yang Tang,Chen-Yuan Gong,Chun-Pu Zou,Lin Su,Xiao Chen,Xiao-Ning Jiao,Lu-Yao Wei,Chao Yao,Xian-Dan Zhu,Carlo Cervellati

doi:10.1155/2021/8856326

Abstract

Non-small-cell lung cancer (NSCLC) remains the most common malignancy with the highest morbidity and mortality worldwide. In our previous study, we found that a classic traditional Chinese medicine (TCM) formula Ze-Qi-Tang (ZQT), which has been used in the treatment of respiratory diseases for thousands of years, could directly inhibit the growth of human NSCLC cells via the p53 signaling pathway. In this study, we explored the immunomodulatory functions of ZQT. We found that ZQT significantly prolonged the survival of orthotopic lung cancer model mice by modulating the tumor microenvironment (TME). ZQT remarkably reduced the number of MDSCs (especially G-MDSCs) and inhibited their immunosuppressive activity by inducing apoptosis in these cells via the STAT3/S100A9/Bcl-2/caspase-3 signaling pathway. When G-MDSCs were depleted, the survival promotion effect of ZQT and its inhibitory effect on lung luminescence signal disappeared in tumor-bearing mice. This is the first study to illustrate the immunomodulatory effect of ZQT in NSCLC and the underlying molecular mechanism.

Highlights

Lung cancer is a serious malignant lung disease, and is the leading cause of cancer death in men and women worldwide [1]
We found that ZQT treatment changed the profile of immune cells in tumor microenvironment (TME): Myeloidderived suppressor cells (MDSCs) were significantly decreased due to apoptosis, which led to a remarkably increased population of CD8+ T cells
We found that after ZQT treatment, the protein levels of pSTAT3, Arg-1, and S100A9 that are tightly associated with G-MDSCs were significantly downregulated, while the content of CD107α and IFN-γ of CD8+ T cells was markedly upregulated

Summary

Introduction

Lung cancer is a serious malignant lung disease, and is the leading cause of cancer death in men and women worldwide [1]. Non-small-cell lung cancer (NSCLC) accounts for 85-90% of all lung cancers [2]. The 5-year survival rate of early-stage NSCLC patients who received surgical excision of the tumor is 36%-83%, depending on the stage of the disease [3]. Current treatment for NSCLC is mainly a comprehensive regimen of chemoradiotherapy, targeted therapy, and immunotherapy. These interventions often have strong side effects [4,5,6], and after the treatment, patients are still at risk of relapse and drug resistance. At present, accumulating researches indicate that TCM therapy can obviously improve the quality of life of NSCLC patients, significantly prolong their survival, and apparently alleviate the clinical

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