Green Tea Polyphenol EGCG Attenuates MDSCs-mediated Immunosuppression through Canonical and Non-Canonical Pathways in a 4T1 Murine Breast Cancer Model.

Ping Xu,Feng Yan,Shili Sun,Xiangbo Chen,Le Ying,Yueling Zhao,Yuefei Wang

doi:10.3390/nu12041042

Abstract

Several studies in the past decades have reported anti-tumor activity of the bioactive compounds extracted from tea leaves, with a focus on the compound epigallocatechin-3-gallate (EGCG). However, further investigations are required to unravel the underlying mechanisms behind the anti-tumor activity of EGCG. In this study, we demonstrate that EGCG significantly inhibits the growth of 4T1 breast cancer cells in vitro and in vivo. EGCG ameliorated immunosuppression by significantly decreasing the accumulation of myeloid-derived suppressor cells (MDSCs) and increasing the proportions of CD4+ and CD8+ T cells in spleen and tumor sites in 4T1 breast tumor-bearing mice. Surprisingly, a low dose of EGCG (0.5–5 μg/mL) effectively reduced the cell viability and increased the apoptosis rate of MDSCs in vitro. EGCG down-regulated the canonical pathways in MDSCs, mainly through the Arg-1/iNOS/Nox2/NF-κB/STAT3 signaling pathway. Moreover, transcriptomic analysis suggested that EGCG also affected the non-canonical pathways in MDSCs, such as ECM–receptor interaction and focal adhesion. qRT-PCR further validated that EGCG restored nine key genes in MDSCs, including Cxcl3, Vcan, Col4a1, Col8a1, Oasl2, Mmp12, Met, Itsnl and Acot1. Our results provide new insight into the mechanism of EGCG-associated key pathways/genes in MDSCs in the murine breast tumor model.

Highlights

Tea (Camellia sinensis) has become one of the most consumed beverages in the world, because of its special flavor, and for its potential benefits to human health, such as preventing cancers [1,2]
4T1 cells were treated with different concentrations of EGCG for 24 h in vitro, the inhibitory effect of EGCG on 4T1 cells was evaluated by CCK8 assay
Having demonstrated that EGCG could efficiently suppress the survival of myeloid-derived suppressor cells (MDSCs), we further investigated the novel/non-canonical pathways that EGCG affected

Summary

Introduction

Tea (Camellia sinensis) has become one of the most consumed beverages in the world, because of its special flavor, and for its potential benefits to human health, such as preventing cancers [1,2]. Epigallocatechin-3-gallate (EGCG) is a fundamental polyphenol compound present in green tea, which was first reported in 1987 to exhibit anti-tumor effects. Numerous studies have investigated the role of EGCG’s anti-tumor function which have suggested that ECGC plays a role in Nutrients 2020, 12, 1042; doi:10.3390/nu12041042 www.mdpi.com/journal/nutrients. Nutrients 2020, 12, 1042 effectively retarding the growth and progression of tumors in vitro and in vivo, even in some human clinical trials [2,3]. Proposed possible mechanisms behind this anti-tumor function include cellular proliferation and apoptosis, modulation of cellular signaling pathways, inhibition of the growth of blood vessels and attenuation of oxidative DNA damage [4]. The mechanisms behind the anti-tumor function of ECGC remain elusive because of the poor bioavailability of ECGC in vivo, and the effective concentration of ECGC in vitro (> 20 μM) could not be reached in animals or humans [5–7]

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