State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Life Sci. 2021 Feb 15;267:118953. doi: 10.1016/j.lfs.2020.118953. Epub 2020 Dec 24.
Cetuximab improves the survival of patients with advanced colorectal cancer (CRC). However, how cetuximab affects the tumor microenvironment has not been sufficiently understood. This study was to investigate whether cetuximab could inhibit the pro-tumor function of tumor-associated macrophages (TAMs) by suppressing the EGFR/IL-6 pathway.
The azoxymethane/dextran sodium sulfate (AOM/DSS) and tumor xenograft mouse models were used to assess the effect of cetuximab on TAMs. Flow cytometry, Western blotting, RT-qPCR, and ELISA were used to assess the prevalence of M2 and M1 phenotypes. Publicly available datasets of CRC patients were used to assess the relevance of EGFR and IL-6 expression as prognostic indicators.
The two mouse models showed that cetuximab could attenuate the pro-tumor function of TAMs and decrease tumor burden. Cetuximab repolarized TAMs from M2-like to M1-like phenotypes, mainly by suppressing the IL-6 expression through NFκB and STAT3 pathways. Analysis of public scRNA-seq data indicated EGFR was mainly expressed on the surface of macrophage infiltration into tumor microenvironment. The public transcriptomics datasets showed that the expression level of IL-6 was positively correlated with EGFR in CRC patients, and PROGgeneV2 analysis indicated that IL-6 and CD206 both predicted poor recurrence-free and overall survival of CRC patients. Furthermore, the inhibition efficacy of cetuximab was significantly attenuated in IL-6 knockout CRC mice model.
These results indicate a new macrophage-based molecular mechanism explaining the effect of cetuximab in treatment of colorectal cancer.
西妥昔单抗可改善晚期结直肠癌（CRC）患者的生存。然而，西妥昔单抗如何影响肿瘤微环境尚未得到充分理解。本研究旨在探讨西妥昔单抗是否可以通过抑制 EGFR/IL-6 通路来抑制肿瘤相关巨噬细胞（TAMs）的促肿瘤功能。
使用氧化偶氮甲烷/葡聚糖硫酸钠（AOM/DSS）和肿瘤异种移植小鼠模型来评估西妥昔单抗对 TAMs 的作用。流式细胞术、Western blot、RT-qPCR 和 ELISA 用于评估 M2 和 M1 表型的流行率。使用 CRC 患者的公共数据集来评估 EGFR 和 IL-6 表达作为预后指标的相关性。
这两个小鼠模型表明，西妥昔单抗可以减弱 TAMs 的促肿瘤功能并降低肿瘤负担。西妥昔单抗通过 NFκB 和 STAT3 通路抑制 IL-6 的表达，将 TAMs 从 M2 样表型重新极化到 M1 样表型。对公共 scRNA-seq 数据的分析表明，EGFR 主要在巨噬细胞浸润肿瘤微环境的表面表达。公共转录组学数据集显示，CRC 患者中 IL-6 的表达水平与 EGFR 呈正相关，PROGgeneV2 分析表明，IL-6 和 CD206 均预测 CRC 患者无复发生存和总体生存不良。此外，在 IL-6 敲除 CRC 小鼠模型中，西妥昔单抗的抑制效果明显减弱。
这些结果表明了一种新的基于巨噬细胞的分子机制，解释了西妥昔单抗在治疗结直肠癌中的作用。
