Chamaejasmenin B, an Inhibitor for Metastatic Outgrowth, Reversed M2-Dominant Macrophage Polarization in Breast Tumor Microenvironment.

Qi Li,Yujie Li,Qingsen Ran,Ying Chen,Xinke Du,Qing Yang,Li Liu,Xiaoxin Zhu,Lidong Sun,Xiaogang Weng,Yajie Wang,Weiyan Cai

doi:10.3389/fimmu.2021.774230

Abstract

Metastasis is a multistep process that depends on the interactions between tumor cells and their microenvironment. Macrophages in the tumor microenvironment show high polarization plasticity and have a paradoxical role in cancer progression. Hijacked by tumor-promoting signals, the polarization status of macrophages was pathologically disturbed and believed to be the decisive mechanism forcing the progression of metastasis. In this study, we explored the immunological activity of Chamaejasmin B (ICJ), a previously proved inhibitor for metastasis, in macrophages from metastatic microenvironment. When intravenously injected of 4T1 cells in mice, ICJ significantly inhibited its metastatic outgrowth. Taking tumor cell and macrophage as a functional integrity, an adoptive transfer model was established in vitro to exclude the direct effect of ICJ on tumor. The findings suggest a dual influence of ICJ on both tumors and macrophages, as indicated by the rebalance of macrophage polarization and suppression of clonogenic potential in tumor cells. Mechanistically, ICJ redirected M2-dominant polarization of tumor-associated macrophage in an IL-4-mTOR-dependent manner. Collectively, our study revealed that ICJ rebalanced macrophage polarization in malignant microenvironment and showed promising effect in suppressing metastatic outgrowth in breast cancer model.

Highlights

Metastasis is the key event in malignancy and is responsible for most cancer-related deaths
We demonstrated the immunological effects of immunological activity of Chamaejasmin B (ICJ) on tumor microenvironment (TME)-mediated macrophage polarization
We firstly evaluated the effects of ICJ on breast cancer metastatic outgrowth in vivo by directly injecting 4T1 cells into the tail vein of female Balb/c mice

Summary

Introduction

Metastasis is the key event in malignancy and is responsible for most cancer-related deaths. Tumor-associated macrophage (TAM), which is the most abundant immune cell in the TME, has both anti- and protumor effects [10] and is negatively correlated with clinical outcomes [11]. During tumor progression, TAMs resemble alternatively activated M2-like macrophages that contribute to malignant angiogenesis, tumor cell intra/extravasation, and outgrowth [14, 15]. In both the spontaneous genetic model of breast cancer metastasis and the orthotopic syngeneic transplant model, breast cancer progression and metastasis can be hindered via the modulation of TAM polarization [16]. Macrophage polarization is an appealing target for metastatic intervention and is a common focus of both experimental and clinical studies [17]

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Results

Conclusion