Ni, Wang, and Stojanovic et al. show that HIF-1α suppresses NK cell activation and effector function and promotes tumor growth. ScRNAseq showed increased activation markers (IFNγ, NF-κB, and Iκbζ) in HIF-1α-deficient mouse NK cells, which was dependent on myeloid cells-derived IL-18. Ex-vivo treatment of human NK cells with HIF-1α inhibitor enhanced IFNγ, TNFα, and CD107a expression, and HIF-1α expression in tumor-infiltrating NK cells negatively correlated with an NK-IL18-IFNG gene signature in NSCLC patients. The NK-IL18-IFNGhigh gene signature was associated with increased OS in patients with melanoma, breast, and cervical cancer.
Contributed by Shishir Pant
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-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.
Author Info: (1) Department of Immunobiochemistry, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany; Innate Immunit
Author Info: (1) 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. (2) Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (3) 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. (4) Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (5) Department of Immunobiochemistry, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany. (6) Innate Immunity, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (7) Innate Immunity, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (8) 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. (9) 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. (10) 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. (11) Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, University of Veterinary Medicine, 1210 Vienna, Austria. (12) Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (13) 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.
