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

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

  • JCI Insight. 2022 Oct 20;e157285. doi: 10.1172/jci.insight.157285.
Ching-Yun Hsieh 1 Ching-Chan Lin 1 Yu-Wen Huang 2 Jong-Hang Chen 1 Yung-An Tsou 3 Ling-Chu Chang 4 Chi-Chen Fan 5 Chen-Yuan Lin 1 Wei-Chao Chang 4
Affiliations

Affiliations

  • 1 Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan.
  • 2 Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan.
  • 3 Department of Otolaryngology-Head and Neck Surgery, China Medical University Hospital, China Medical University, Taichung, Taiwan.
  • 4 Center for Molecular Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan.
  • 5 Department of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical Technology, Hsinchu, Taiwan.
Abstract

Docetaxel (DTX) combined with cisplatin and 5-FU 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 was significantly associated with shorter overall survival and increased resistance to chemotherapeutic drugs, particularly DTX in HNSCC patients. Macrophage co-culture 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 co-culture. IL-1β activated superoxide dismutase 2 and inhibited catalase, thereby modulating intracellular levels of Reactive Oxygen Species (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.

Keywords

Cancer; Drug therapy; Macrophages; Oncology.

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