Single-Cell RNA Sequencing of Tumor-Infiltrating NK Cells Reveals that Inhibition of Transcription Factor HIF-1α Unleashes NK Cell Activity
Open accessAbstract
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.
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32-134D inhibited the expression of CD47, CD70, IL-6, and IL-10 mRNAs in immune or other stromal cell types, where HIFs play critical roles, rather than in tumor cells.
“which suggests that 32-134D inhibited the expression of these latter mRNAs in immune or other stromal cell types, where HIFs are known to play critical roles (56–61), rather than in tumor cells.”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [59]
Considerable evidence in mouse models has shown that hypoxia promotes tumor escape from immune surveillance and immunotherapy.
“Considerable evidence in mouse models has shown that hypoxia promotes tumor escape from immune surveillance and immunotherapy13–19.”
There are opposite reports showing that tumor hypoxia induces mouse T cell exhaustion and resistance to immunotherapy and depletion of HIF1α increases NK cell activity and tumor infiltration.
“there are also opposite reports showing that tumor hypoxia induces mouse T cell exhaustion and resistance to immunotherapy and depletion of HIF1α increases NK cell activity and tumor infiltration16,17,19,48,49.”
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- Authors
- Ni, J., Wang, X., Stojanovic, A., Zhang, Q., Wincher, M., Bühler, L., Arnold, A., Correia, M. P., Winkler, M., Koch, P.-S., Sexl, V., Höfer, T., & Cerwenka, A.
- Affiliations
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- University of Veterinary Medicine Vienna (AT)
- Corresponding author
- Cerwenka, Adelheid
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2020-06
- Volume
- 52
- Issue
- 6
- Pages
- 1075-1087.e8
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W3026991696
- Cited by
- 324
- References
- 59
- Citations by year
- 2026: 46 · 2025: 56 · 2024: 54 · 2023: 46 · 2022: 68 · 2021: 45 · 2020: 8
- FWCI
- 14.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Commission (H2020-MSCA-MC-ITN-765104-MATURE-NK)
- Deutsche Forschungsgemeinschaft (B10N, TP07, CE 140/2-2, SFB1366, TRR179, 259332240-RTG2099, P9, SFB-TRR156, RTG 2099, 394046768-SFB 1366)
- Universitätsmedizin Mannheim
- Deutsches Krebsforschungszentrum
- Deutsche Krebshilfe (111455, 70112233)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- tumor-infiltrating NK cells, HIF-1α, hypoxia, NF-κB signaling, IL-18, interferon-gamma, HIF-1α inhibition, antitumor immunity, cancer immunotherapy, transcriptional landscape, tumor microenvironment
- MeSH terms
- Animals, Cytotoxicity, Immunologic, Humans, Killer Cells, Natural, Lymphocyte Activation, Neoplasms, Prognosis, Biomarkers, Cytokines, Lymphocytes, Tumor-Infiltrating, Mice, Knockout, Computational Biology, Myeloid Cells, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Single-Cell Analysis, High-Throughput Nucleotide Sequencing, Tumor Microenvironment, Transcriptome
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