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Macrophage secretory IL-1β promotes docetaxel resistance in head and neck squamous carcinoma via SOD2/CAT-ICAM1 signaling
Ching-Yun Hsieh, … , Chen-Yuan Lin, Wei-Chao Chang
Ching-Yun Hsieh, … , Chen-Yuan Lin, Wei-Chao Chang
Published October 20, 2022
Citation Information: JCI Insight. 2022;7(23):e157285. https://doi.org/10.1172/jci.insight.157285.
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Research Article Oncology

Macrophage secretory IL-1β promotes docetaxel resistance in head and neck squamous carcinoma via SOD2/CAT-ICAM1 signaling

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Abstract

Docetaxel (DTX) combined with cisplatin and 5-fluorouracil has been used as induction chemotherapy for head and neck squamous cell carcinoma (HNSCC). However, the development of acquired resistance remains a major obstacle to treatment response. Tumor-associated macrophages are associated with chemotherapeutic resistance. In the present study, increased infiltration of macrophages into the tumor microenvironment (TME) was significantly associated with shorter overall survival and increased resistance to chemotherapeutic drugs, particularly DTX, in patients with HNSCC. Macrophage coculture induced expression of intercellular adhesion molecule 1 (ICAM1), which promotes stemness and the formation of polyploid giant cancer cells, thereby reducing the efficacy of DTX. Both genetic silencing and pharmacological inhibition of ICAM1 sensitized HNSCC to DTX. Macrophage secretion of IL-1β was found to induce tumor expression of ICAM1. IL-1β neutralization and IL-1 receptor blockade reversed DTX resistance induced by macrophage coculture. IL-1β activated superoxide dismutase 2 and inhibited catalase, thereby modulating intracellular levels of ROS and inducing ICAM1 expression. Arsenic trioxide (ATO) reduced macrophage infiltration into the TME and impaired IL-1β secretion by macrophages. The combinatorial use of ATO enhanced the in vivo efficacy of DTX in a mouse model, which may provide a revolutionary approach to overcoming acquired therapeutic resistance in HNSCC.

Authors

Ching-Yun Hsieh, Ching-Chan Lin, Yu-Wen Huang, Jong-Hang Chen, Yung-An Tsou, Ling-Chu Chang, Chi-Chen Fan, Chen-Yuan Lin, Wei-Chao Chang

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Figure 2

CM-induced ICAM1 increases tumor stemness in HNSCC.

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CM-induced ICAM1 increases tumor stemness in HNSCC.
(A) Pearson’s correl...
(A) Pearson’s correlation between commonly identified proteins in both comparative proteomic analyses analyzed using log2 ratio of abundance changes. (B) Heatmap clustering analysis of quantified proteins with significant abundance ratios (P < 0.05) in both comparative proteomes. (C) Scatterplots demonstrating the relationship between ratio weights and abundance ratios for each identified protein in the proteomic analysis. The color of protein dots represents the P value for corresponding abundance ratios. (D) ICAM1 expression in OECM-1 cells cocultured with THP-1–derived macrophages and PBMC M1-like or M2-like macrophages. (E) Spearman’s monotonic correlation between ICAM1 and CD163 expression in HNSCC analyzed using the TCGA RNA-Seq database on the GEPIA server. TPM, transcripts per million. ICAM1 in FaDu, OECM-1, and CE146 cells induced by (F) CM or (G) 20% CM at different periods. (H) Spheroid formation in FaDu and SAS cells in the presence or absence of 20% CM for 12 days (n = 3). (I) Number of spheroids formed in ICAM1-KD and control CE146T cells in the presence or absence of 20% CM for 12 days (n = 3). The effect of ICAM1 inhibition by shRNA was validated (right). Effects of (J) 20% CM treatment and (K) ICAM1-KD on CD44 expression in FaDu and OECM-1 cells. (L) mRNA levels of ZEB1 and ZEB2 in OECM-1 cells treated with CM determined by quantitative PCR and normalized to untreated control (set as 1, dashed line). GAPDH, β-actin, and 18S rRNA mRNA were internal controls for gene expression. (M) Levels of EMT-related proteins in OECM-1 cells induced by CM. β-actin, loading control. (N) Transwell migration and (O) invasion assays performed using OECM-1 cells in the presence or absence of 10% CM. Signal quantification with crystal violet extract measured by colorimetric analysis at 570 nm (n = 3). Means ± SD. Two-tailed unpaired Student’s t test (H, I, N, and O). **, P < 0.01.

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