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

• Type of Material: Article
• Authors: Luis Ruffolo, University of Rochester; Katherine M Jackson, University of Rochester; Peyton C Kuhlers, University of North Carolina; Benjamin S Dale, University of Rochester; Nathania Figueroa Guilliani, Providence Portland Medical Center; Nicholas A Ullman, University of Rochester; Paul R Burchard, University of Rochester; Shuyang S Qin, University of Rochester; Peter G Juviler, University of Rochester; Jessica Millian Keilson, Emory University; Ashely B Morrison, Univ North Carolina Syst; Mary Georger, University of Rochester; Rachel Jewell, University of Rochester; Laura M Calvi, University of Rochester; Timothy M Nywening, University of Pittsburgh; Michael R O'Dell, University of Rochester; Aram F Hezel, University of Rochester; Luis De Las Casas, Univ Texas Southwestern Med Ctr Dallas; Gregory Lesinski, Emory University; Jen Jen Yeh, Univ North Carolina Syst; Roberto Hernandez-Alejandro, University of Rochester; Brian A Belt, University of Rochester; David C Linehan, University of Rochester
• Language: English
• Date: 2021-08-19
• Publisher: BMJ PUBLISHING GROUP
• Publication Version: Final Published Version
• Copyright Statement: © 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.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1136/gutjnl-2021-324109
• Title of Journal or Parent Work: GUT
• Volume: 71
• Issue: 7
• Start Page: 1386
• End Page: 1398
• Grant/Funding Information: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
• Keywords: RECEPTOR; immunotherapy; cholangiocarcinoma; EXPRESSION; macrophages; IL-3; PANCREATIC-CANCER; inflammatory mediators; immune response; Science & Technology; IMMUNOTHERAPY; Gastroenterology & Hepatology; STROMA; Life Sciences & Biomedicine; PROMOTES
• Research Categories: Health Sciences, Oncology; Health Sciences, Medicine and Surgery

Abstract

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.