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

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 4

CM enhances ICAM1 expression through modulation of intracellular ROS levels.

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CM enhances ICAM1 expression through modulation of intracellular ROS lev...
(A) Mitochondrial superoxide levels and (B) intracellular ROS levels in FaDu cells with or without 20% CM treatment were determined using the tracer dyes, MitoSOX (Invitrogen) and CM-H2DCFDA (DCF, Invitrogen), respectively. (C) The expression of ICAM1 in FaDu and OECM-1 cells with or without 5 mM NAC pretreatment in the presence or absence of 20% CM for 24 hours was determined by Western blotting. (D) The expression levels of SOD1, SOD2, and CAT in FaDu and OECM-1 cells treated with indicated doses of CM were determined by Western blotting. (E) Intracellular ROS levels in FaDu and OECM-1 cells in the presence or absence of 20% CM or 30 μM PIO were determined using the tracer dye, DCF, by flow cytometry. (F) The protein levels of ICAM1 and CAT in FaDu and OECM-1 cells in the presence or absence of indicated doses of CM or 30 or 60 μM PIO were determined by Western blotting. β-actin, loading control. (G) Spheroid formation and (H) cell invasion of FaDu and OECM-1 cells with or without 30 μM PIO treatment. (I) Cell viability of FaDu and OECM-1 cells in the presence or absence of 20% CM or 30 μM PIO for 24 hours 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 (A, B, G, and H) or 1-way ANOVA with Tukey’s post hoc test (E and I) was used. *, P < 0.05; **, P < 0.01.