Normoxic to hypoxic switch of pre-activated NK cells leads to robust proliferation and enhanced effector function via stabilization of HIF-1α and inhibition of apoptosis

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Abstract Although mature NK cells can function within hypoxic lymphatics and tissues, they show impaired anti-tumor functions in ex-vivo hypoxic environments. This raises a question regarding additional cues that may exist to allow full NK cell activation within the hypoxic tumor microenvironment. Here, we provide evidence that pre-activation of NK cells prior to hypoxic exposure is key to overcoming hypoxia-mediated impairment and inducing greater NK cell proliferation with enhanced cytolytic activity. Specifically, exposing pre-activated NK cells to 1.5% of pO2 hypoxia following 7-9 days of normoxic culture allowed HIF-1α stabilization and its target gene expression, leading to specific upregulation of NKp44 activating receptor and increased STAT3 phosphorylation. These hypoxia-exposed NK cells demonstrate concomitant reduction of apoptotic and p21/p53 senescence pathways, resulting in greater cell numbers in culture. Therefore, pre-existing proliferative signals allows HIF-1α-mediated adaptation of NK cells toward highly proliferative and cytolytic phenotypes, which may occur in vivo throughout tumor immunosurveillance.