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

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

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 5

Macrophage secretory IL-1β induces ICAM1 in HNSCC.

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Macrophage secretory IL-1β induces ICAM1 in HNSCC. (A) Cytokine levels i...
(A) Cytokine levels in CM from monocultures of FaDu or THP-1, or FaDu–THP-1 coculture, were analyzed by Luminex Multi-Analyte Profiling (xMAP) system. (B) Expression levels of ICAM1 in OECM-1 cells induced by various kinds of cytokines were determined by Western blotting. (C) Expression levels of ICAM1 in different HNSCC cell lines induced by 3 ng/mL IL-1β were determined by Western blotting. (D) Expression levels of SOD and CAT in FaDu and OECM-1 cells induced by 3 ng/mL IL-1β were determined by Western blotting. Mitochondrial superoxide levels and (B) intracellular ROS levels in OECM-1 cells in the presence or absence of 3 ng/mL IL-1β were monitored using the tracer dyes, (E) MitoSOX and (F) DCF. (G) Expression levels of ICAM1 and CAT in OECM-1 cells in the presence or absence of 3 ng/mL IL-1β or 30 μM PIO for 24 hours were determined by Western blotting. (H) Expression levels of ICAM1, SOD2, and CAT in OECM-1 cells in the presence or absence of 20% CM or 50 nM anakinra for 24 hours were determined by Western blotting. β-actin, loading control. Viability of OECM-1 cells with or without 20% CM treatment in the presence or absence of (I) 50 nM anakinra or (J) 3 ng/mL IL-1β neutralizing antibody (4H5; InvivoGen) was determined under indicated doses of DTX by MTT assay. Data were displayed as the means ± SD. For statistical analyses, a 2-tailed unpaired Student’s t test (E and F) or 1-way ANOVA with Tukey’s post hoc test (I and J) was used. *, P < 0.05; **, P < 0.01.