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

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

  • Gut. 2022 Jul;71(7):1386-1398. doi: 10.1136/gutjnl-2021-324109.
Luis I Ruffolo 1,  Katherine M Jackson 1,  Peyton C Kuhlers 2,  Benjamin S Dale 1,  Nathania M Figueroa Guilliani 3,  Nicholas A Ullman 1,  Paul R Burchard 1,  Shuyang S Qin 4,  Peter G Juviler 1,  Jessica Millian Keilson 5,  Ashley B Morrison 6,  Mary Georger 7,  Rachel Jewell 1,  Laura M Calvi 7,  Timothy M Nywening 8,  Michael R O'Dell 7,  Aram F Hezel 7,  Luis De Las Casas 9,  Gregory B Lesinski 10,  Jen Jen Yeh 11,  Roberto Hernandez-Alejandro 1,  Brian A Belt 1,  David C Linehan 12
Affiliations

Affiliations

  • 1 Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA.
  • 2 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.
  • 3 Department of Surgery, Providence Portland Medical Center, Portland, Oregon, USA.
  • 4 Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA.
  • 5 Division of Surgical Oncology, Department of Surgery, Emory University, Atlanta, Georgia, USA.
  • 6 Lineberger Comprehensive Cancer Center, University of North Carolina System, Chapel Hill, North Carolina, USA.
  • 7 Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA.
  • 8 Division of Surgical Oncology, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
  • 9 Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • 10 Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.
  • 11 Departments of Surgery and Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina System, Chapel Hill, North Carolina, USA.
  • 12 Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA David_Linehan@URMC.Rochester.edu.
PMID: 34413131 DOI: 10.1136/gutjnl-2021-324109
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.

Keywords

cholangiocarcinoma; immune response; immunotherapy; inflammatory mediators; macrophages.

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