Upregulation of MTA1 in Colon Cancer Drives A CD8+ T Cell-Rich But Classical Macrophage-Lacking Immunosuppressive Tumor Microenvironment.

Peng Nan,Fei Ma,Haijuan Wang,Ying Zhang,Chunxiao Li,Hongnan Mo,Yantong Zhou,Dongkui Xu,Haili Qian

doi:10.3389/fonc.2022.825783

Abstract

BackgroundThe MTA1 protein encoded by metastasis-associated protein 1 (MTA1) is a key component of the ATP-dependent nucleosome remodeling and deacetylase (NuRD) complex, which is widely upregulated in cancers. MTA1 extensively affects downstream gene expression by participating in chromatin remodeling. Although it was defined as a metastasis-associated gene in first reports and metastasis is a process prominently affected by the tumor microenvironment, whether it affects the microenvironment has not been investigated. In our study, we elucidated the regulatory effect of MTA1 on tumor-associated macrophages (TAMs) and how this regulation affects the antitumor effect of cytotoxic T lymphocytes (CTLs) in the tumor microenvironment of colorectal cancer.MethodsWe detected the cytokines affected by MTA1 expression via a cytokine antibody array in control HCT116 cells and HCT116 cells overexpressing MTA1. Multiplex IHC staining was conducted on a colorectal cancer tissue array from our cancer cohort. Flow cytometry (FCM) was performed to explore the polarization of macrophages in the coculture system and the antitumor killing effect of CTLs in the coculture system. Bioinformatics analysis was conducted to analyze the Cancer Genome Atlas (TCGA) colorectal cancer cohort and single-cell RNA-seq data to assess the immune infiltration status of the TCGA colorectal cancer cohort and the functions of myeloid cells.ResultsMTA1 upregulation in colorectal cancer was found to drive an immunosuppressive tumor microenvironment. In the tumor microenvironment of MTA1-upregulated colorectal cancer, although CD8+ T cells were significantly enriched, macrophages were significantly decreased, which impaired the CTL effect of the CD8+ T cells on tumor cells. Moreover, upregulated MTA1 in tumor cells significantly induced infiltrated macrophages into tumor-associated macrophage phenotypes and further weakened the cytotoxic effect of CD8+ T cells.ConclusionUpregulation of MTA1 in colorectal cancer drives an immunosuppressive tumor microenvironment by decreasing the microphages from the tumor and inducing the residual macrophages into tumor-associated microphage phenotypes to block the activation of the killing CTL, which contributes to cancer progression.

Highlights

With the development of cancer research, the concept of the tumor microenvironment and its importance in tumor progression and tumor treatment is increasingly being recognized [1]
metastasis-associated protein 1 (MTA1) is generally overexpressed in tumors, and in colorectal cancer (Figure 1A), and the MTA1 expression level is negatively correlated with the overall survival of the patients in the colorectal cancer cohort (Figure 1B)
Among the results derived from various immune infiltration evaluation algorithms, the expression level of MTA1 in colorectal cancer was significantly positively correlated with the level of CD8+ T cell infiltration and negatively correlated with macrophage infiltration (Figure 1C)

Summary

Introduction

With the development of cancer research, the concept of the tumor microenvironment and its importance in tumor progression and tumor treatment is increasingly being recognized [1]. An inflamed but still immunosuppressive microenvironment can be potentially fueled by various myeloid cells, tumor-associated macrophages (TAMs) [4, 5]. Drivers of these different immunomodulatory scenarios are not well defined. MTA1 extensively affects downstream gene expression by participating in chromatin remodeling It was defined as a metastasis-associated gene in first reports and metastasis is a process prominently affected by the tumor microenvironment, whether it affects the microenvironment has not been investigated. We elucidated the regulatory effect of MTA1 on tumorassociated macrophages (TAMs) and how this regulation affects the antitumor effect of cytotoxic T lymphocytes (CTLs) in the tumor microenvironment of colorectal cancer

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