The Immune-microenvironment Confers Chemoresistance of Colorectal Cancer through Macrophage-Derived IL6

Abstract

Tumor-associated macrophages (TAMs) are frequently associated with poor prognosis in human cancers. However, the effects of TAMs in colorectal cancer are contradictory. We therefore investigated the functions, mechanisms, and clinical significance of TAMs in colorectal cancer. We measured the macrophage infiltration (CD68), P-gp, and Bcl2 expression in colorectal cancer tissues using IHC staining. Coculture of TAMs and colorectal cancer cells both and models was used to evaluate the effects of TAMs on colorectal cancer chemoresistance. Cytokine antibody arrays, ELISA, neutralizing antibody, and luciferase reporter assay were performed to uncover the underlying mechanism. TAM infiltration was associated with chemoresistance in patients with colorectal cancer. Colorectal cancer-conditioned macrophages increased colorectal cancer chemoresistance and reduced drug-induced apoptosis by secreting IL6, which could be blocked by a neutralizing anti-IL6 antibody. Macrophage-derived IL6 activated the IL6R/STAT3 pathway in colorectal cancer 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 colorectal cancer chemoresistance. miR-155-5p, a key miRNA regulating C/EBPβ, was frequently downregulated in TAMs, resulting in increased C/EBPβ expression. C/EBPβ transcriptionally activated IL6 in TAMs, and TAM-secreted IL6 then induced chemoresistance by activating the IL6R/STAT3/miR-204-5p pathway in colorectal cancer cells. Our data indicate that the maladjusted miR-155-5p/C/EBPβ/IL6 signaling in TAMs could induce chemoresistance in colorectal cancer cells by regulating the IL6R/STAT3/miR-204-5p axis, revealing a new cross-talk between immune cells and tumor cells in colorectal cancer microenvironment. .

Long non‐coding RNA PCAT6 targets miR‐204 to modulate the chemoresistance of colorectal cancer cells to 5‐fluorouracil‐based treatment through HMGA2 signaling

“…Moreover, the activity of IL‐6R/STAT3/miR‐204 feedback loop is correlated with chemo‐sensitivity of epithelial ovarian cancer . In another research on tumor‐related macrophages in CRC, the maladjusted miR‐155‐5p/C/EBPβ/IL‐6 signaling could induce chemoresistance in CRC cells by regulating the IL‐6R/STAT3/miR‐204‐5p axis . Through direct binding to ZEB1, miR‐204 modulates chemo‐sensitivity and apoptosis of prostate cancer cells .…”

“…43 In another research on tumor-related macrophages in CRC, the maladjusted miR-155-5p/C/EBPβ/IL-6 signaling could induce chemoresistance in CRC cells by regulating the IL-6R/STAT3/miR-204-5p axis. 44 Through direct binding to ZEB1, miR-204 modulates chemo-sensitivity and apoptosis of prostate cancer cells. 45 We have revealed that PCAT6 directly binds to miR-204 to inhibit its expression; herein, we also assessed the combined effect of PCAT6 and miR-204 on the chemoresistance of CRC cells to 5-FU.…”

M2‐polarized tumor‐associated macrophages promote epithelial‐mesenchymal transition via activation of the AKT3/PRAS40 signaling pathway in intrahepatic cholangiocarcinoma

“…Furthermore, our data demonstrated that four cytokines (IL‐6, TNF‐α, GM‐CSF[CSF2], and ICAM‐1) had close relation with AKT and its substrate PRAS40 phosphorylation in ICC cells. IL‐6 is one of the most well‐characterized cytokines in the TME . Activation of the IL‐6 signaling has been proven to result into a range of carcinogenic effects, including induction EMT .…”

“…IL-6 is one of the most well-characterized cytokines in the TME. [25][26][27][28] Activation of the IL-6 signaling has been proven to result into a range of carcinogenic effects, including induction EMT. [29][30][31] Previous studies have also provided clear F I G U R E 5 AKT inhibitor VIII markedly inhibited M2-polarized TAMs-induced EMT.…”

Curcumin-Loaded Solid Lipid Nanoparticles Bypass P-Glycoprotein Mediated Doxorubicin Resistance in Triple Negative Breast Cancer Cells

“…Tumor associated macrophages (TAMs) are known to play an important role in inducing chemoresistance [46]. To verify whether the chemosensitizing effects of CURC-loaded SLNs were still preserved in the presence of infiltrating macrophages, we set up co-cultures of THP-1-derived macrophages, which phenotypically recapitulated TAM populations [47].…”