PMID- 32445619
OWN - NLM
STAT- MEDLINE
DCOM- 20210322
LR  - 20210322
IS  - 1097-4180 (Electronic)
IS  - 1074-7613 (Linking)
VI  - 52
IP  - 6
DP  - 2020 Jun 16
TI  - Single-Cell RNA Sequencing of Tumor-Infiltrating NK Cells Reveals that Inhibition 
      of Transcription Factor HIF-1alpha Unleashes NK Cell Activity.
PG  - 1075-1087.e8
LID - S1074-7613(20)30182-5 [pii]
LID - 10.1016/j.immuni.2020.05.001 [doi]
AB  - Enhancing immune cell functions in tumors remains a major challenge in cancer 
      immunotherapy. Hypoxia is a common feature of solid tumors, and cells adapt by 
      upregulating the transcription factor HIF-1alpha. Here, we defined the 
      transcriptional landscape of mouse tumor-infiltrating natural killer (NK) cells 
      by using single-cell RNA sequencing. Conditional deletion of Hif1a in NK cells 
      resulted in reduced tumor growth, elevated expression of activation markers, 
      effector molecules, and an enriched NF-kappaB pathway in tumor-infiltrating NK cells. 
      Interleukin-18 (IL-18) from myeloid cells was required for NF-kappaB activation and 
      the enhanced anti-tumor activity of Hif1a(-/-) NK cells. Extended culture with an 
      HIF-1alpha inhibitor increased human NK cell responses. Low HIF1A expression was 
      associated with high expression of IFNG in human tumor-infiltrating NK cells, and 
      an enriched NK-IL18-IFNG signature in solid tumors correlated with increased 
      overall patient survival. Thus, inhibition of HIF-1alpha unleashes NK cell anti-tumor 
      activity and could be exploited for cancer therapy.
CI  - Copyright (c) 2020 Elsevier Inc. All rights reserved.
FAU - Ni, Jing
AU  - Ni J
AD  - Department of Immunobiochemistry, Mannheim Institute for Innate Immunoscience 
      (MI3), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, 
      Germany; Innate Immunity, German Cancer Research Center (DKFZ), 69120 Heidelberg, 
      Germany.
FAU - Wang, Xi
AU  - Wang X
AD  - Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), 
      69120 Heidelberg, Germany.
FAU - Stojanovic, Ana
AU  - Stojanovic A
AD  - Department of Immunobiochemistry, Mannheim Institute for Innate Immunoscience 
      (MI3), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, 
      Germany; Innate Immunity, German Cancer Research Center (DKFZ), 69120 Heidelberg, 
      Germany.
FAU - Zhang, Qin
AU  - Zhang Q
AD  - Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), 
      69120 Heidelberg, Germany.
FAU - Wincher, Marian
AU  - Wincher M
AD  - Department of Immunobiochemistry, Mannheim Institute for Innate Immunoscience 
      (MI3), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, 
      Germany.
FAU - Buhler, Lea
AU  - Buhler L
AD  - Innate Immunity, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
FAU - Arnold, Annette
AU  - Arnold A
AD  - Innate Immunity, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
FAU - Correia, Margareta P
AU  - Correia MP
AD  - Department of Immunobiochemistry, Mannheim Institute for Innate Immunoscience 
      (MI3), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, 
      Germany; Innate Immunity, German Cancer Research Center (DKFZ), 69120 Heidelberg, 
      Germany.
FAU - Winkler, Manuel
AU  - Winkler M
AD  - Department of Dermatology, Venereology, and Allergology, University Medical 
      Center and Medical Faculty Mannheim, University of Heidelberg, and Center of 
      Excellence in Dermatology, 68167 Mannheim, Germany.
FAU - Koch, Philipp-Sebastian
AU  - Koch PS
AD  - Department of Dermatology, Venereology, and Allergology, University Medical 
      Center and Medical Faculty Mannheim, University of Heidelberg, and Center of 
      Excellence in Dermatology, 68167 Mannheim, Germany; European Center for 
      Angioscience (ECAS), Medical Faculty Mannheim, University of Heidelberg, 68167 
      Mannheim, Germany.
FAU - Sexl, Veronika
AU  - Sexl V
AD  - Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, 
      University of Veterinary Medicine, 1210 Vienna, Austria.
FAU - Hofer, Thomas
AU  - Hofer T
AD  - Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), 
      69120 Heidelberg, Germany.
FAU - Cerwenka, Adelheid
AU  - Cerwenka A
AD  - Department of Immunobiochemistry, Mannheim Institute for Innate Immunoscience 
      (MI3), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, 
      Germany; Innate Immunity, German Cancer Research Center (DKFZ), 69120 Heidelberg, 
      Germany; European Center for Angioscience (ECAS), Medical Faculty Mannheim, 
      University of Heidelberg, 68167 Mannheim, Germany. Electronic address: 
      adelheid.cerwenka@medma.uni-heidelberg.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200522
PL  - United States
TA  - Immunity
JT  - Immunity
JID - 9432918
RN  - 0 (Biomarkers)
RN  - 0 (Cytokines)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
SB  - IM
CIN - Immunity. 2020 Jun 16;52(6):895-897. PMID: 32553176
MH  - Animals
MH  - Biomarkers
MH  - Computational Biology
MH  - Cytokines/metabolism
MH  - *Cytotoxicity, Immunologic
MH  - High-Throughput Nucleotide Sequencing
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
MH  - Killer Cells, Natural/*immunology/*metabolism
MH  - Lymphocyte Activation/genetics/*immunology
MH  - Lymphocytes, Tumor-Infiltrating/*immunology/*metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Myeloid Cells/immunology/metabolism
MH  - Neoplasms/immunology/metabolism/mortality
MH  - Prognosis
MH  - Single-Cell Analysis
MH  - Transcriptome
MH  - Tumor Microenvironment/immunology
OTO - NOTNLM
OT  - HIF-1alpha
OT  - IFN-gamma
OT  - IL-18
OT  - NF-kappaB
OT  - NK cells
OT  - natural killer cells
OT  - single-cell RNA sequencing
OT  - tumor immunology
OT  - tumor microenvironment
COIS- Declaration of Interests The authors declare no competing interests.
EDAT- 2020/05/24 06:00
MHDA- 2021/03/23 06:00
CRDT- 2020/05/24 06:00
PHST- 2019/01/28 00:00 [received]
PHST- 2020/02/19 00:00 [revised]
PHST- 2020/04/30 00:00 [accepted]
PHST- 2020/05/24 06:00 [pubmed]
PHST- 2021/03/23 06:00 [medline]
PHST- 2020/05/24 06:00 [entrez]
AID - S1074-7613(20)30182-5 [pii]
AID - 10.1016/j.immuni.2020.05.001 [doi]
PST - ppublish
SO  - Immunity. 2020 Jun 16;52(6):1075-1087.e8. doi: 10.1016/j.immuni.2020.05.001. Epub 
      2020 May 22.