期刊
GUT
卷 71, 期 7, 页码 1386-1398出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2021-324109
关键词
cholangiocarcinoma; immunotherapy; macrophages; immune response; inflammatory mediators
Intrahepatic cholangiocarcinoma (iCCA) is characterized by infiltration of suppressive myeloid populations, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Tumors overexpress granulocyte-macrophage colony-stimulating factor (GM-CSF) which promotes an immunosuppressive microenvironment, but blocking GM-CSF shows promise in promoting anti-tumor immunity and regression.
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.
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