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Macrophage Differentiation and Polarization into an M2-Like Phenotype using a Human Monocyte-Like THP-1 Leukemia Cell Line
Published on: August 2, 2021
RSK4 promotes the macrophage recruitment and M2 polarization in esophageal squamous cell carcinoma
Shuai He1, Ming Lu2, Liang Zhang3
1State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an, China; Department of Pathology, Baotou Medical college, Baotou, Inner Mongolia Autonomous Region, China.
Abstract:
High infiltration of tumor-associated macrophages (TAMs) participates in host immunity and tumor progression in patients with esophageal squamous cell carcinoma (ESCC). Ribosomal s6 kinase 4 (RSK4) has been shown to be aberrantly overexpressed in ESCC. The role of RSK4 in cytokine secretion and its impact on macrophage recruitment and M2 polarization remains unclear. Therefore, a thorough understanding of RSK4 is needed to expand our knowledge of its therapeutic potential. Herein, RSK4 expression in human ESCC tissues and a xenograft mouse model was positively correlated with high infiltration of M0 and M2 macrophages which is positively associated with unfavorable overall survival outcomes and treatment resistance in patients with ESCC. In vitro experiments revealed that RSK4 derived from ESCC cells promoted macrophage recruitment and M2 polarization by enhancingsoluble intercellular adhesion molecule-1 (sICAM-1) secretion via direct and indirect STAT3 phosphorylation. Furthermore, RSK4-induced macrophages enhanced tumor proliferation, migration, and invasion by secreting C-C motif chemokine ligand 22 (CCL22). We further showed that patients with elevated CD68 and CD206 expression had unfavorable overall survival. Collectively, these results demonstrate that RSK4 promotes the macrophage recruitment and M2 polarization by regulating the STAT3/ICAM-1 axis in ESCC, influencing tumor progression primarily in a CCL22-dependent manner. These data also offer valuable insights for developing novel agents for the treatment of ESCC.
Insights
Ribosomal s6 kinase 4 (RSK4) drives esophageal squamous cell carcinoma (ESCC) progression by promoting macrophage recruitment and M2 polarization. Targeting RSK4 may offer new therapeutic strategies for ESCC treatment.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- High infiltration of tumor-associated macrophages (TAMs) is linked to host immunity and tumor progression in esophageal squamous cell carcinoma (ESCC).
- Aberrant overexpression of Ribosomal s6 kinase 4 (RSK4) is observed in ESCC, but its role in macrophage polarization and recruitment is not fully understood.
- Understanding RSK4's function is crucial for exploring its therapeutic potential in ESCC.
Purpose of the Study:
- To investigate the role of RSK4 in macrophage recruitment and M2 polarization in ESCC.
- To elucidate the molecular mechanisms by which RSK4 influences ESCC progression.
- To assess the correlation between RSK4 expression, macrophage infiltration, and patient outcomes in ESCC.
Main Methods:
- Analysis of RSK4 expression in human ESCC tissues and a xenograft mouse model.
- In vitro experiments to assess RSK4's effect on macrophage recruitment and M2 polarization.
- Investigation of the STAT3/ICAM-1 axis and CCL22 secretion in RSK4-mediated effects.
Main Results:
- RSK4 expression positively correlated with M0 and M2 macrophage infiltration, unfavorable survival, and treatment resistance in ESCC patients.
- RSK4 promoted macrophage recruitment and M2 polarization by enhancing soluble intercellular adhesion molecule-1 (sICAM-1) secretion via STAT3 phosphorylation.
- RSK4-induced macrophages enhanced tumor proliferation, migration, and invasion through C-C motif chemokine ligand 22 (CCL22) secretion.
Conclusions:
- RSK4 promotes macrophage recruitment and M2 polarization in ESCC by regulating the STAT3/ICAM-1 axis.
- RSK4 influences ESCC progression in a CCL22-dependent manner.
- These findings suggest RSK4 as a potential therapeutic target for ESCC treatment.
