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.

中文翻译：

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CCL2-CCR2轴募集肿瘤相关的巨噬细胞，通过食管癌变过程中的PD-1信号传导诱导免疫逃逸。

背景技术食管鳞状细胞癌（ESCC）的预后较差，突出表明需要针对这种疾病的新策略。我们先前的研究表明CCL2和肿瘤相关巨噬细胞（TAMs）参与食管癌变。尽管TAM被公认为是癌症治疗的有希望的靶标，但是其在ESCC中的浸润，激活和肿瘤促进功能的机制仍未知。方法采用人食管组织阵列和TCGA数据库评估食管鳞癌中CCL2和TAMs的临床相关性。用N-亚硝基甲基苄胺（NMBA）处理F344大鼠和C57BL / 6小鼠，以建立食管癌变的原位模型。CCL2 / CCR2基因敲除小鼠和巨噬细胞特异性PPARG基因敲除小鼠分别用于研究TAM在ESCC中的浸润和极化作用。估计在恶性转化的Het-1A细胞中，CCL2介导的单核细胞趋化性。THP-1细胞用于体外模拟TAM极化。进行RNA测序以揭示该机制。结果食管癌变过程中CCL2表达的增加与TAM的蓄积有关，它们都预示着食管癌预后不良。动物研究表明，阻断CCL2-CCR2轴可通过阻止TAM募集而大大降低肿瘤发生率，从而增强CD8 + T细胞在肿瘤微环境中的抗肿瘤功效。更重要的是，M2极化增加了TAM中PD-L2的表达，通过PD-1信号通路导致免疫逃避和肿瘤促进。结论本研究强调了CCL2-CCR2轴在食管癌变中的作用。我们的发现为ESCA中TAM介导的免疫逃逸机制提供了新的见解，表明以TAMs为靶点的ESCC预防和免疫治疗策略的潜力。