Suppressive myeloid cells are expanded by biliary tract cancer-derived cytokines in vitro and associate with aggressive disease

• Published in: British journal of cancer Vol. 123; no. 9; pp. 1377 - 1386
• Main Authors: Ware, Michael B., Zaidi, Mohammad Y., Yang, Jennifer, Turgeon, Michael K., Krasinskas, Alyssa, Mace, Thomas A., Keenan, Kaitlin, Farren, Matthew R., Ruggieri, Amanda N., Li, Yiman, Zhang, Chao, Chen, Zhengjia, Young, Gregory S., Elnaggar, Omar, Che, Zheng, Maithel, Shishir K., Bekaii-Saab, Tanios, El-Rayes, Bassel, Lesinski, Gregory B.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.10.2020; Nature Publishing Group
• Subjects: 631/250; 631/67/327; Biliary tract; Biliary Tract Neoplasms - metabolism; Biliary Tract Neoplasms - pathology; Biomedical and Life Sciences; Biomedicine; Calgranulin B - metabolism; Cancer Research; Cell Count; Cell Proliferation - drug effects; Cells, Cultured; Cholangiocarcinoma; Culture Media, Conditioned - metabolism; Culture Media, Conditioned - pharmacology; Cytokines; Cytokines - metabolism; Cytokines - pharmacology; Drug Resistance; Epidemiology; Flow cytometry; Granulocyte-macrophage colony-stimulating factor; Histocompatibility antigen HLA; Humans; Immunomodulation; Interleukin 6; Leukocytes (mononuclear); Lymphocyte Activation - drug effects; Molecular Medicine; Monocyte chemoattractant protein 1; Myeloid cells; Myeloid Cells - drug effects; Myeloid Cells - pathology; Myeloid Cells - physiology; Myeloid-Derived Suppressor Cells - drug effects; Myeloid-Derived Suppressor Cells - pathology; Myeloid-Derived Suppressor Cells - physiology; Neoplasm Grading; Neoplasm Invasiveness; Oncology; Peripheral blood mononuclear cells; Sialic Acid Binding Ig-like Lectin 3 - metabolism; Signal transduction; Stat3 protein; Suppressor cells
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-020-1018-0

Background BTC is an aggressive disease exacerbated by inflammation and immune suppression. Expansion of immunosuppressive cells occurs in biliary tract cancer (BTC), yet the role of BTC-derived cytokines in this process is unclear. Methods Activated signalling pathways and cytokine production were evaluated in a panel of human BTC cell lines. Human peripheral blood mononuclear cells (PBMCs) were cultured with BTC supernatants, with and without cytokine neutralising antibodies, and analysed by flow cytometry or immunoblot. A human BTC tissue microarray (TMA, n  = 69) was stained for IL-6, GM-CSF, and CD33 + S100a9 + cells and correlated with clinical outcomes. Results Immunomodulatory factors (IL-6, GM-CSF, MCP-1) were present in BTC supernatants. BTC supernatants expanded CD33 dim CD11b + HLA-DR low/− myeloid-derived suppressor cells (MDSCs) from human PBMCs. Neutralisation of IL-6 and GM-CSF in BTC supernatants inhibited activation of STAT3/5, respectively, in PBMCs, with heterogeneous effects on MDSC expansion in vitro. Staining of a BTC TMA revealed a positive correlation between IL-6 and GM-CSF, with each cytokine and more CD33 + S100a9 + cells. Increased CD33 + S100a9 + staining positively correlated with higher tumour grade, differentiation and the presence of satellite lesions. Conclusion BTC-derived factors promote suppressive myeloid cell expansion, and higher numbers of CD33 + S100a9 + cells in resectable BTC tumours correlates with more aggressive disease.