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 6

ATO reduces IL-1β secretion from macrophages.

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ATO reduces IL-1β secretion from macrophages. THP-1–differentiated macro...
THP-1–differentiated macrophages cocultured with FaDu cells were treated with indicated dose of chemotherapeutic agents including Asadin (ATO), axitinib, atezolizumab, and cabozantinib. (A) Expression levels of pro–IL-1β in macrophages were determined by Western blotting. (B) Levels of mature IL-1β in CM were measured using ELISA kits (ARG80101; Arigo Biolaboratories). (C) Expression levels of ICAM1 in OECM-1 cells with or without 20% CM treatment in the presence or absence of 1 μM ATO for 24 hours were determined by Western blot assay. (D) Expression levels of ICAM1 in OECM-1 cells with or without coculture with THP-1–differentiated macrophages in the presence or absence of 1 μM ATO for 24 hours were determined by Western blotting. Expression levels of (E) caspase-1 and (F) autophagy-related proteins such as ULK1, LC3B, and p62 in THP-1–differentiated macrophages treated with indicated doses of ATO were determined by Western blotting. β-Actin, loading control. Data were displayed as the means ± SD. For statistical analysis, 1-way ANOVA with Tukey’s post hoc test (B) was used. **, P < 0.01.