Macrophage-derived CCL22 promotes an immunosuppressive tumor microenvironment via IL-8 in malignant pleural effusion

• Published in: Cancer letters Vol. 452; pp. 244 - 253
• Main Authors: Wang, Dong, Yang, Li, Yue, Dongli, Cao, Ling, Li, Lifeng, Wang, Dan, Ping, Yu, Shen, Zhibo, Zheng, Yujia, Wang, Liping, Zhang, Yi
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 28.06.2019; Elsevier Limited
• Subjects: c-Fos protein; CCL22; CCL22 protein; Cell Line, Tumor; Cellular biology; Chemokine CCL22 - metabolism; Chemokines; Cytokines; Cytotoxicity; Flow cytometry; Humans; IL-8; Immune Tolerance - immunology; Immunoglobulins; Immunoregulation; Immunosuppressive agents; Immunosuppressive tumor microenvironment; Interleukin 8; Interleukin-8 - metabolism; Lung cancer; Lung Neoplasms - pathology; Lymphocytes; Lymphocytes T; Macrophage; Macrophages; Macrophages - metabolism; Malignant pleural effusion; Pleural effusion; Pleural Effusion, Malignant - pathology; R&D; Research & development; T-Lymphocytes, Regulatory - immunology; THP-1 Cells; Transforming Growth Factor beta - metabolism; Tumor Microenvironment - immunology; United States > US; Japan; CCL22; IL-8; Malignant pleural effusion; Immunosuppressive tumor microenvironment; Macrophage
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2019.03.040

Immune dysfunction often occurs in malignant pleural effusion (MPE). In our previous study, TGF-β derived predominantly from macrophages plays an important role in impairing T cell cytotoxicity in MPE. Therefore, we aimed to investigate whether other immunoregulatory cells and factors mediated TGF-β secretion from macrophages, involved in the immunosuppressive microenvironment of MPE, and to provide clues for potential immune therapy for MPE as well. We found that CCL22 level in MPE was significantly higher than that in non-malignant pleural effusion. The high level of CCL22 was closely associated with poor survival in MPE patients with lung cancer. CCL22 was dominantly produced by tumor-associated macrophages (TAMs) in MPE. Meanwhile, TAM-derived TGF-β mediated CCL22 expression in TAMs via c-Fos. CCL22 promoted the recruitment of regulatory T cells (Tregs) in MPE. Lastly, Treg-secreted high level of IL-8 further induced TGF-β production from TAMs, and promoted the immunosuppressive tumor microenvironment in MPE. Our results indicate that macrophage-derived CCL22 plays an important role in the immunosuppressive tumor microenvironment via IL-8 in MPE. •MPE exhibits a high level of CCL22, which is dominantly derived from TAMs.•TAM-derived TGF-β induces CCL22 expression in TAMs via c-Fos in MPE.•CCL22 further promotes the recruitment of Tregs in MPE.•Treg-produced IL-8 induces the secretion of TGF-β by TAMs, which promotes an immunosuppressive tumor microenvironment in MPE.•It will provide a rationale for therapeutic targeting of the CCL22/IL-8 pathway for MPE.