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

• Published in: Immunity (Cambridge, Mass.) Vol. 52; no. 6; pp. 1075 - 1087.e8
• Main Authors: Ni, Jing, Wang, Xi, Stojanovic, Ana, Zhang, Qin, Wincher, Marian, Bühler, Lea, Arnold, Annette, Correia, Margareta P., Winkler, Manuel, Koch, Philipp-Sebastian, Sexl, Veronika, Höfer, Thomas, Cerwenka, Adelheid
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.06.2020; Elsevier Limited
• Subjects: Activation; Angiogenesis; Animals; Anticancer properties; Antitumor agents; Biomarkers; Cancer; Cancer immunotherapy; Cell culture; Clonal deletion; Computational Biology; Cytokines; Cytokines - metabolism; Cytotoxicity, Immunologic; Gene sequencing; Genotype & phenotype; Growth factors; HIF-1α; High-Throughput Nucleotide Sequencing; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; IFN-γ; IL-18; Immune system; Immunotherapy; Interleukin 1; Interleukin 18; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Melanoma; Mice; Mice, Knockout; Myeloid cells; Myeloid Cells - immunology; Myeloid Cells - metabolism; Natural killer cells; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - mortality; NF-κB; NF-κB protein; NK cells; Prognosis; Ribonucleic acid; RNA; Single-Cell Analysis; single-cell RNA sequencing; Solid tumors; Transcription factors; Transcriptome; tumor immunology; tumor microenvironment; Tumor Microenvironment - immunology; Tumors; single-cell RNA sequencing; natural killer cells; NF-κB; NK cells; IFN-γ; tumor immunology; IL-18; HIF-1α; tumor microenvironment
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2020.05.001

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. [Display omitted] •Hif1a deficiency in NK cells reduces tumor growth•Single-cell RNA sequencing reveals activated Hif1a−/− NK cells in tumor•IL-18 drives high NF-κB, Iκbζ, and Ifng expression in tumor HIF1a−/− NK cells•An NK-IL18-IFNGhi signature correlates with increased survival in cancer patients Ni et al. define the transcriptional landscape of tumor-infiltrating NK cells using single-cell RNA sequencing. They find that the transcription factor HIF-1α suppresses IL-18-driven NF-κB signaling and anti-tumor activity of tumor-infiltrating NK cells. Extended inhibition of HIF-1α in mouse or human NK cells unleashes potent NK cell effector function.