Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma

David Kung-Chun Chiu, Aki Pui-Wah Tse, Iris Ming-Jing Xu, Jane Cui, Robin Kit-Ho Lai, Lynna Lan Li, Hui-Yu Koh, Felice Ho-Ching Tsang, Larry Lai Wei, Chun-Ming Wong, Irene Oi-Lin Ng () and Carmen Chak-Lui Wong ()
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David Kung-Chun Chiu: The University of Hong Kong
Aki Pui-Wah Tse: The University of Hong Kong
Iris Ming-Jing Xu: The University of Hong Kong
Jane Cui: The University of Hong Kong
Robin Kit-Ho Lai: The University of Hong Kong
Lynna Lan Li: The University of Hong Kong
Hui-Yu Koh: The University of Hong Kong
Felice Ho-Ching Tsang: The University of Hong Kong
Larry Lai Wei: The University of Hong Kong
Chun-Ming Wong: The University of Hong Kong
Irene Oi-Lin Ng: The University of Hong Kong
Carmen Chak-Lui Wong: The University of Hong Kong

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Myeloid-derived suppressor cells (MDSCs) possess immunosuppressive activities, which allow cancers to escape immune surveillance and become non-responsive to immune checkpoints blockade. Here we report hypoxia as a cause of MDSC accumulation. Using hepatocellular carcinoma (HCC) as a cancer model, we show that hypoxia, through stabilization of hypoxia-inducible factor-1 (HIF-1), induces ectoenzyme, ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2/CD39L1), in cancer cells, causing its overexpression in HCC clinical specimens. Overexpression of ENTPD2 is found as a poor prognostic indicator for HCC. Mechanistically, we demonstrate that ENTPD2 converts extracellular ATP to 5′-AMP, which prevents the differentiation of MDSCs and therefore promotes the maintenance of MDSCs. We further find that ENTPD2 inhibition is able to mitigate cancer growth and enhance the efficiency and efficacy of immune checkpoint inhibitors. Our data suggest that ENTPD2 may be a good prognostic marker and therapeutic target for cancer patients, especially those receiving immune therapy.

Date: 2017
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DOI: 10.1038/s41467-017-00530-7

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