Aims: 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.
Main methods: 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.
Key findings: 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.
Significance: These results indicate a new macrophage-based molecular mechanism explaining the effect of cetuximab in treatment of colorectal cancer.
Keywords: AOM/DSS; Cetuximab; Colorectal cancer; IL-6; Tumor associated macrophages.
Copyright © 2020. Published by Elsevier Inc.