The Immune-microenvironment Confers Chemoresistance of Colorectal Cancer through Macrophage-derived IL-6

Purpose: Tumor-associated macrophages (TAMs) are frequently associated with poor prognosis in human cancers. However, the effects of TAM in colorectal cancer (CRC) are contradictory. We therefore investigated the functions, mechanisms and clinical significance of TAMs in CRC. Experimental Design: We measured the macrophage infiltration (CD68), P-gp and Bcl2 expression in CRC tissues using Immunohistochemistry staining. Co-culture of TAMs and CRC cells both in vitro and in vivo models was used to evaluate the effects of TAMs on CRC chemoresistance. Cytokine Antibody Arrays, enzyme linked immunosorbent assay, neutralizing antibody and luciferase reporter assay were performed to uncover the underlying mechanism. Results: TAM infiltration was associated with chemoresistance in CRC patients. CRC-conditioned macrophages increased CRC chemoresistance and reduced drug-induced apoptosis by secreting IL-6, which could be blocked by a neutralizing anti-IL-6 antibody. Macrophage-derived IL-6 activated the IL-6R/STAT3 pathway in CRC cells, and activated STAT3 transcriptionally inhibited the tumor suppressor miR-204-5p. Rescue experiment confirmed that miR-204-5p is a functional target mediating the TAM-induced CRC chemoresistance. miR-155-5p, a key microRNA regulating C/EBPβ, was frequently downregulated in TAM, resulting in increased C/EBPβ expression. C/EBPβ transcriptionally activated IL-6 in TAM, and TAM-secreted IL-6 then induced chemoresistance by activating the IL-6R/STAT3/miR-204-5p pathway in CRC cells. Conclusions: Our data indicate that the maladjusted miR-155-5p/C/EBPβ/IL-6 signaling in TAM could induce chemoresistance in CRC cells by regulating the IL-6R/STAT3/miR-204-5p axis, revealing a new crosstalk between immune cells and tumor cells in CRC microenvironment.

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