The Interleukin-33/ST2 Axis Enhances Lung-Resident CD14+ Monocyte Function in Patients with Non-Small Cell Lung...

Interleukin-33 (IL-33) binds to its cognate receptor suppression of tumorigenicity 2 (ST2), leading to critical modulatory roles in immune responses during inflammation and cancers. The aim of this study was to investigate the role of IL-33/ST2 signaling in monocyte function in non-small cell lung cancer (NSCLC). Sixty-two NSCLC patients and nineteen controls were enrolled. IL-33 levels and ST2 expression were measured in peripheral blood and bronchoalveolar lavage fluid (BALF) by ELISA and flow cytometry. HLA-DR expression by CD14+ monocytes, granzyme B and proinflammatory cytokine secretion were also investigated in lipopolysaccharide-stimulated cells. CD14+ monocytes purified from BALF in the tumor site were stimulated with IL-33 in vitro, and co-cultured with a lung cancer cell line A549 cells. The cytotoxicity of monocytes with IL-33 stimulation was then assessed. IL-33 levels were lower in the peripheral blood and tumor microenvironment of NSCLC patients. There was no significant difference in peripheral ST2 expression between NSCLC patients and controls. Soluble ST2 levels were increased but membrane-bound ST2 expression in CD14+ monocytes was decreased in tumor microenvironment of NSCLC patients. There were no remarkable differences in either HLA-DR expression or proinflammatory cytokine secretion by circulating CD14+ monocytes between NSCLC patients and controls. CD14+ monocytes in the tumor microenvironment revealed a dysfunctional phenotype, which presented as lower HLA-DR expression and reduced granzyme B and proinflammatory cytokines. A higher concentration of IL-33 stimulation promoted tumor-resident CD14+ monocyte-induced target cell death. The present study indicates that IL-33/ST2 signaling pathway might enhance the activity of tumor-resident CD14+ monocytes in NSCLC.