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-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: head and neck squamous cell carcinoma (HNSCC), docetaxel (DTX), tumor associated macrophage (TAM), IL-1β, intercellular adhesion molecule 1 (ICAM1), arsenic trioxide (ATO).

HPV-Negative and HPV-Positive Oral Cancer Cells Stimulate the Polarization of Neutrophils towards Different Functional Phenotypes In Vitro

“…In this regard, TNF-α may contribute to tumor progression by acting together with TGF-β to induce endothelial-to-mesenchymal transition [30]. IL-1β is involved in regulating epithelialmesenchymal transition, metastasis [31], and chemotherapy resistance [32]. IL-6 promotes the activation of the STAT3 pathway, thereby promoting tumor cell proliferation [33].…”

Macrophage: Hidden Criminal in Therapy Resistance

“…In this regard, Jinushi et al [ 27 ] reported that milk fat globule-epidermal growth factor-VIII (MFG-E8) secreted from TAMs activated STAT3 and Sonic Hedgehog signaling in cancer stem cells, limiting their sensitivity to cisplatin in mice. Macrophage-derived interleukin-1β (IL-1β) upregulated intercellular adhesion molecule 1 (ICAM1) expression on tumor cells to promote their stemness, endowing the chemoresistant property of head and neck squamous cell carcinoma [ 28 ].…”

Panoramic view of key cross-talks underpinning the oral squamous cell carcinoma stemness - unearthing the future opportunities

“…Upon ICAM1 activation, mesenchymal markers such as fibronectin, N-cadherin, and vimentin were observed to be elevated whereas, epithelial marker (E-cadherin) was suppressed, reinforcing the increased EMT features. Further, the IL-1β-SOD2/CAT-ICAM1 pathway is exemplified to contribute to chemoresistance towards docetaxel ( 136 ). TAM markers, CD68 and CD163 were highly expressed in OSCC samples in comparison to normal oral mucosa and dysplastic cell samples.…”