GM-CSF drives myelopoiesis, recruitment and polarisation of tumour-associated macrophages in cholangiocarcinoma and systemic blockade facilitates antitumour immunity.
oregon; portland; ppmc; chiles
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
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.
Ruffolo, Luis I; Jackson, Katherine M; Kuhlers, Peyton C; Dale, Benjamin S; Figueroa Guilliani, Nathania M; Ullman, Nicholas A; Burchard, Paul R; Qin, Shuyang S; Juviler, Peter G; Keilson, Jessica Millian; Morrison, Ashley B; Georger, Mary; Jewell, Rachel; Calvi, Laura M; Nywening, Timothy M; O'Dell, Michael R; Hezel, Aram F; De Las Casas, Luis; Lesinski, Gregory B; Yeh, Jen Jen; Hernandez-Alejandro, Roberto; Belt, Brian A; and Linehan, David C, "GM-CSF drives myelopoiesis, recruitment and polarisation of tumour-associated macrophages in cholangiocarcinoma and systemic blockade facilitates antitumour immunity." (2021). Articles, Abstracts, and Reports. 5185.