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Single-cell RNA sequencing of tumor-infiltrating NK cells reveals that inhibition of transcription factor HIF-1α unleashes NK cell activity

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-1α. Here, we defined the transcriptional landscape of mouse tumor-infiltrating natural killer (NK) ce...

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Main Authors: Ni, Jing (Author) , Wang, Xi (Author) , Stojanovic, Ana (Author) , Zhang, Qin (Author) , Wincher, Marian (Author) , Bühler, Lea (Author) , Arnold, Annette (Author) , Correia, Margareta (Author) , Winkler, Manuel (Author) , Reiners-Koch, Philipp-Sebastian (Author) , Sexl, Veronika (Author) , Höfer, Thomas (Author) , Cerwenka, Adelheid (Author)
Format: Article (Journal)
Language:English
Published: 22 May 2020
In: Immunity
Year: 2020, Volume: 52, Issue: 6, Pages: 1075-1087.e8
ISSN:1097-4180
DOI:10.1016/j.immuni.2020.05.001
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.immuni.2020.05.001
Verlag, lizenzpflichtig, Volltext: http://www.sciencedirect.com/science/article/pii/S1074761320301825
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Author Notes:authors: Jing Ni, Xi Wang, Ana Stojanovic, Qin Zhang, Marian Wincher, Lea Bühler, Annette Arnold, Margareta P. Correia, Manuel Winkler, Philipp-Sebastian Koch, Veronika Sexl, Thomas Höfer and Adelheid Cerwenka
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Summary: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-1α. 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-κB pathway in tumor-infiltrating NK cells. Interleukin-18 (IL-18) from myeloid cells was required for NF-κB activation and the enhanced anti-tumor activity of Hif1a−/− NK cells. Extended culture with an HIF-1α 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-1α unleashes NK cell anti-tumor activity and could be exploited for cancer therapy.
Item Description:Gesehen am 27.10.2020
Physical Description:Online Resource
ISSN:1097-4180
DOI:10.1016/j.immuni.2020.05.001

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