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.