GM-CSF drives myelopoiesis, recruitment and polarisation of tumour-associated macrophages in cholangiocarcinoma and systemic blockade facilitates antitumour immunity.

Autor:	Ruffolo LI; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Jackson KM; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Kuhlers PC; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA., Dale BS; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Figueroa Guilliani NM; Department of Surgery, Providence Portland Medical Center, Portland, Oregon, USA., Ullman NA; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Burchard PR; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Qin SS; Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA., Juviler PG; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Keilson JM; Division of Surgical Oncology, Department of Surgery, Emory University, Atlanta, Georgia, USA., Morrison AB; Lineberger Comprehensive Cancer Center, University of North Carolina System, Chapel Hill, North Carolina, USA., Georger M; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA., Jewell R; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Calvi LM; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA., Nywening TM; Division of Surgical Oncology, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA., O'Dell MR; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA., Hezel AF; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA., De Las Casas L; Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA., Lesinski GB; Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA., Yeh JJ; Departments of Surgery and Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina System, Chapel Hill, North Carolina, USA., Hernandez-Alejandro R; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Belt BA; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Linehan DC; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA David_Linehan@URMC.Rochester.edu.
Jazyk:	angličtina
Zdroj:	Gut [Gut] 2022 Jul; Vol. 71 (7), pp. 1386-1398. Date of Electronic Publication: 2021 Aug 19.
DOI:	10.1136/gutjnl-2021-324109
Abstrakt:	Objective: Intrahepatic cholangiocarcinoma (iCCA) is rising in incidence, and at present, there are limited effective systemic therapies. iCCA tumours are infiltrated by stromal cells, with high prevalence of suppressive myeloid populations including tumour-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Here, we show that tumour-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) and the host bone marrow is central for monopoiesis and potentiation of TAMs, and abrogation of this signalling axis facilitates antitumour immunity in a novel model of iCCA. Methods: Blood and tumours were analysed from iCCA patients and controls. Treatment and correlative studies were performed in mice with autochthonous and established orthotopic iCCA tumours treated with anti-GM-CSF monoclonal antibody. Results: Systemic elevation in circulating myeloid cells correlates with poor prognosis in patients with iCCA, and patients who undergo resection have a worse overall survival if tumours are more infiltrated with CD68 + TAMs. Mice with spontaneous iCCA demonstrate significant elevation of monocytic myeloid cells in the tumour microenvironment and immune compartments, and tumours overexpress GM-CSF. Blockade of GM-CSF with a monoclonal antibody decreased tumour growth and spread. Mice bearing orthotopic tumours treated with anti-GM-CSF demonstrate repolarisation of immunosuppressive TAMs and MDSCs, facilitating T cell response and tumour regression. GM-CSF blockade dampened inflammatory gene networks in tumours and TAMs. Human tumours with decreased GM-CSF expression exhibit improved overall survival after resection. Conclusions: iCCA uses the GM-CSF-bone marrow axis to establish an immunosuppressive tumour microenvironment. Blockade of the GM-CSF axis promotes antitumour T cell immunity. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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