PMID- 28894087
OWN - NLM
STAT- MEDLINE
DCOM- 20180222
LR  - 20181113
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 8
IP  - 1
DP  - 2017 Sep 11
TI  - Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells 
      accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma.
PG  - 517
LID - 10.1038/s41467-017-00530-7 [doi]
LID - 517
AB  - 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.Myeloid-derived suppressor cells (MDSCs) promote tumor immune escape. 
      Here, the authors show that in hepatocellular carcinoma, hypoxia induces the 
      expression of ENTPD2 on cancer cells leading to elevated extracellular 5'-AMP, 
      which in turn promote the maintenance of MDSCs by preventing their 
      differentiation.
FAU - Chiu, David Kung-Chun
AU  - Chiu DK
AD  - Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong.
FAU - Tse, Aki Pui-Wah
AU  - Tse AP
AD  - Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong.
FAU - Xu, Iris Ming-Jing
AU  - Xu IM
AD  - Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong.
FAU - Di Cui, Jane
AU  - Di Cui J
AD  - Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong.
FAU - Lai, Robin Kit-Ho
AU  - Lai RK
AD  - Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong.
FAU - Li, Lynna Lan
AU  - Li LL
AD  - Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong.
FAU - Koh, Hui-Yu
AU  - Koh HY
AD  - Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong.
FAU - Tsang, Felice Ho-Ching
AU  - Tsang FH
AD  - Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong.
FAU - Wei, Larry Lai
AU  - Wei LL
AD  - Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong.
FAU - Wong, Chun-Ming
AU  - Wong CM
AUID- ORCID: 0000-0002-2497-7858
AD  - Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong.
AD  - State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, 
      Hong Kong.
FAU - Ng, Irene Oi-Lin
AU  - Ng IO
AD  - Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong. 
      iolng@hku.hk.
AD  - State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, 
      Hong Kong. iolng@hku.hk.
FAU - Wong, Carmen Chak-Lui
AU  - Wong CC
AD  - Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong. 
      carmencl@pathology.hku.hk.
AD  - State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, 
      Hong Kong. carmencl@pathology.hku.hk.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170911
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - EC 3.6.1.- (Adenosine Triphosphatases)
RN  - EC 3.6.1.- (ectoATPase)
SB  - IM
MH  - Adenosine Triphosphatases/genetics/*metabolism
MH  - Carcinoma, Hepatocellular/*enzymology/genetics/metabolism/physiopathology
MH  - Cell Differentiation
MH  - Cell Proliferation
MH  - Humans
MH  - Hypoxia/enzymology/genetics/metabolism/physiopathology
MH  - Hypoxia-Inducible Factor 1/genetics/*metabolism
MH  - Liver Neoplasms/*enzymology/genetics/metabolism/physiopathology
MH  - Myeloid-Derived Suppressor Cells/cytology/*enzymology/metabolism
PMC - PMC5593860
COIS- The authors declare no competing financial interests.
EDAT- 2017/09/13 06:00
MHDA- 2018/02/23 06:00
PMCR- 2017/09/11
CRDT- 2017/09/13 06:00
PHST- 2016/11/10 00:00 [received]
PHST- 2017/07/06 00:00 [accepted]
PHST- 2017/09/13 06:00 [entrez]
PHST- 2017/09/13 06:00 [pubmed]
PHST- 2018/02/23 06:00 [medline]
PHST- 2017/09/11 00:00 [pmc-release]
AID - 10.1038/s41467-017-00530-7 [pii]
AID - 530 [pii]
AID - 10.1038/s41467-017-00530-7 [doi]
PST - epublish
SO  - Nat Commun. 2017 Sep 11;8(1):517. doi: 10.1038/s41467-017-00530-7.