TY - JOUR
T1 - Suppressive myeloid cells are expanded by biliary tract cancer-derived cytokines in vitro and associate with aggressive disease
AU - Ware, Michael B.
AU - Zaidi, Mohammad Y.
AU - Yang, Jennifer
AU - Turgeon, Michael K.
AU - Krasinskas, Alyssa
AU - Mace, Thomas A.
AU - Keenan, Kaitlin
AU - Farren, Matthew R.
AU - Ruggieri, Amanda N.
AU - Li, Yiman
AU - Zhang, Chao
AU - Chen, Zhengjia
AU - Young, Gregory S.
AU - Elnaggar, Omar
AU - Che, Zheng
AU - Maithel, Shishir K.
AU - Bekaii-Saab, Tanios
AU - El-Rayes, Bassel
AU - Lesinski, Gregory B.
N1 - Funding Information:
and receives compensation for these services. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies. Dr. El-Rayes has received research funding through a sponsored research agreement between Emory University and Bristol-Myers Squibb, Boston Biomedical, Novartis, Merck and Co, Bayer, Exelixis, Pfizer, AstraZeneca/Medimmune, Incyte, and EUSA.
Funding Information:
Funding information Research reported in this publication was supported under award number P30CA138292 and 1R01 CA228414-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was also supported by funding from The National Institutes of Health, P30CA16058, T32CA090223, and from the William Hall Fund for Liver and Pancreatic Cancer Research.
Funding Information:
Competing interests Dr. Lesinski has consulted for ProDa Biotech, LLC and received compensation. Dr. Lesinski has received research funding through a sponsored research agreement between Emory University and Merck and Co., Inc., Bristol-Myers Squibb, Inc., Boerhinger-Ingleheim, Inc., and Vaccinex, Inc. Dr. El-Rayes has consulted for Ipsen, Merck and Co., BayerAstraZeneca, and Bristol-Myers Squibb, Inc. and has been a speaker for Lexicon, Inc. Dr. El-Rayes serves as a consultant to Merck and Co.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Cancer Research UK.
PY - 2020/10/27
Y1 - 2020/10/27
N2 - 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.
AB - 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.
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U2 - 10.1038/s41416-020-1018-0
DO - 10.1038/s41416-020-1018-0
M3 - Article
C2 - 32747748
AN - SCOPUS:85088869412
SN - 0007-0920
VL - 123
SP - 1377
EP - 1386
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 9
ER -