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. 2020 Jun 16;52(6):1075-1087.e8.
doi: 10.1016/j.immuni.2020.05.001. Epub 2020 May 22.

Single-Cell RNA Sequencing of Tumor-Infiltrating NK Cells Reveals that Inhibition of Transcription Factor HIF-1α Unleashes NK Cell Activity

Jing Ni  1 , Xi Wang  2 , Ana Stojanovic  1 , Qin Zhang  2 , Marian Wincher  3 , Lea Bühler  4 , Annette Arnold  4 , Margareta P Correia  1 , Manuel Winkler  5 , Philipp-Sebastian Koch  6 , Veronika Sexl  7 , Thomas Höfer  2 , Adelheid Cerwenka  8
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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

Jing Ni et al. Immunity. .
Free article

Abstract

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.

Keywords: HIF-1α; IFN-γ; IL-18; NF-κB; NK cells; natural killer cells; single-cell RNA sequencing; tumor immunology; tumor microenvironment.

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Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

Comment in

  • Natural Killers out of Thin Air.
    Nakamura K, Smyth MJ. Nakamura K, et al. Immunity. 2020 Jun 16;52(6):895-897. doi: 10.1016/j.immuni.2020.05.007. Immunity. 2020. PMID: 32553176

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