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

Michael B. Ware, Mohammad Y. Zaidi, Jennifer Yang, Michael K. Turgeon, Alyssa Krasinskas, Thomas A. Mace, Kaitlin Keenan, Matthew R. Farren, Amanda N. Ruggieri, Yiman Li, Chao Zhang, Zhengjia Chen, Gregory S. Young, Omar Elnaggar, Zheng Che, Shishir K. Maithel, Tanios Bekaii-Saab, Bassel El-Rayes, Gregory B. Lesinski

Research output: Contribution to journalArticle

Abstract

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 CD33dimCD11b+HLA-DRlow/− 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.

Original languageEnglish (US)
JournalBritish journal of cancer
DOIs
StateAccepted/In press - 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Ware, M. B., Zaidi, M. Y., Yang, J., Turgeon, M. K., Krasinskas, A., Mace, T. A., Keenan, K., Farren, M. R., Ruggieri, A. N., Li, Y., Zhang, C., Chen, Z., Young, G. S., Elnaggar, O., Che, Z., Maithel, S. K., Bekaii-Saab, T., El-Rayes, B., & Lesinski, G. B. (Accepted/In press). Suppressive myeloid cells are expanded by biliary tract cancer-derived cytokines in vitro and associate with aggressive disease. British journal of cancer. https://doi.org/10.1038/s41416-020-1018-0