Journal Article

CCL2-CCR2 axis recruits tumor associated macrophages to induce immune evasion through PD-1 signaling in esophageal carcinogenesis

Zhang, Xin, Feng, Yongquan, Xu, Miao, Wang, Lei, Jia, Xudong, Zhang, Qiannan, Chen, Xuewei, Li, Yongning, Cui, Wenming, Yang, Hui

2020

Overview

Background The poor prognosis of esophageal squamous cell carcinoma (ESCC) highlights the need for novel strategies against this disease. Our previous study suggested the involvement of CCL2 and tumor associated macrophages (TAMs) in esophageal carcinogenesis. Despite the recognition of TAMs as a promising target for cancer treatment, mechanisms underlying its infiltration, activation and tumor-promotive function in ESCC remain unknown. Methods Human esophageal tissue array and TCGA database were used to evaluate the clinical relevance of CCL2 and TAMs in ESCC. F344 rats and C57BL/6 mice were treated with N-nitrosomethylbenzylamine (NMBA) to establish orthotopic models of esophageal carcinogenesis. CCL2/CCR2 gene knockout mice and macrophage-specific PPARG gene knockout mice were respectively used to investigate the role of infiltration and polarization of TAMs in ESCC. CCL2-mediated monocyte chemotaxis was estimated in malignantly transformed Het-1A cells. THP-1 cells were used to simulate TAMs polarization in vitro. RNA-sequencing was performed to uncover the mechanism. Results Increasing expression of CCL2 correlated with TAMs accumulation in esophageal carcinogenesis, and they both predicts poor prognosis in ESCC cohort. Animal studies show blockade of CCL2-CCR2 axis strongly reduces tumor incidence by hindering TAMs recruitment and thereby potentiates the antitumor efficacy of CD8 + T cells in the tumor microenvironment. More importantly, M2 polarization increases PD-L2 expression in TAMs, resulting in immune evasion and tumor promotion through PD-1 signaling pathway. Conclusion This study highlights the role of CCL2-CCR2 axis in esophageal carcinogenesis. Our findings provide new insight into the mechanism of immune evasion mediated by TAMs in ESCC, suggesting the potential of TAMs-targeted strategies for ESCC prevention and immunotherapy.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Animals / Apoptosis / Biomarkers, Tumor - genetics / Biomarkers, Tumor - metabolism / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cancer treatment / Carcinogenesis / Carcinoma / CCL2 / CCR2 / CCR2 protein / Cell cycle / Cell Proliferation / Chemokine CCL2 - genetics / Chemokine CCL2 - metabolism / Chemokines / Development and progression / Diseases / Esophageal cancer / Esophageal Neoplasms - genetics / Esophageal Neoplasms - immunology / Esophageal Neoplasms - metabolism / Esophageal Neoplasms - pathology / Esophageal squamous cell carcinoma (ESCC) / Esophageal Squamous Cell Carcinoma - genetics / Esophageal Squamous Cell Carcinoma - immunology / Esophageal Squamous Cell Carcinoma - metabolism / Esophageal Squamous Cell Carcinoma - pathology / Esophagus / Gene expression / Gene Expression Regulation, Neoplastic / Genes / House mouse / Humans / Immune evasion / Immunotherapy / Laboratory animals / Macrophages / Male / Medical prognosis / Medical research / Mice / Mice, Inbred C57BL / Monocyte chemoattractant protein 1 / Novels / Oncology / PD-1 protein / Prognosis / Programmed Cell Death 1 Receptor - genetics / Programmed Cell Death 1 Receptor - metabolism / Programmed death-1(PD-1) / Rats / Rats, Inbred F344 / Receptors, CCR2 - genetics / Receptors, CCR2 - metabolism / RNA / Software / Squamous cell carcinoma / Statistical analysis / T cells / Tumor associated macrophages (TAMs) / Tumor Cells, Cultured / Tumor-Associated Macrophages - immunology / Tumor-Associated Macrophages - metabolism / Tumor-Associated Macrophages - pathology / Tumors / Variance analysis