Abstract
Natural killer (NK) cells are cytotoxic innate lymphocytes that are specialized to kill tumor cells. NK cells are responsive to the primary cytokine IL-2 in the tumor microenvironment (TME), to activate its effector functions against tumors. Despite their inherent ability to kill tumor cells, dysfunctional NK cells observed within advanced solid tumors are associated with poor patient survival. Hypoxia in the TME is a major contributor to immune evasion in solid tumors that could contribute to impaired NK cell function. HIF-1α is a nodal regulator of hypoxia in driving the adaptive cellular responses to changes in oxygen concentrations. Whether HIF-1α is expressed in hypoxic NK cells in the context of IL-2 and whether its expression regulates NK cell effector function are unclear. Here, we report that freshly isolated NK cells from human peripheral blood in hypoxia could not stabilize HIF-1α protein coincident with impaired anti-tumor cytotoxicity. However, ex vivo expansion of these cells restored HIF-1α levels in hypoxia to promote antitumor cytotoxic functions. Similarly, the human NK cell line NKL expressed HIF-1α upon IL-2 stimulation in hypoxia and exhibited improved anti-tumor cytotoxicity and IFN-γ secretion. We found that ex vivo expanded human NK cells and NKL cells required the concerted activation of PI3K/mTOR pathway initiated by IL-2 signaling in combination with hypoxia for HIF-1α stabilization. These findings highlight that HIF-1α stabilization in hypoxia maximizes NK cell effector function and raises the prospect of NK cells as ideal therapeutic candidates for solid tumors.
Highlights
Natural killer cells (NK), the major innate effector cells, with their broad cytotoxicity against tumors are ideal candidates for immunotherapy [1, 2]
NK cells are innate immune cells that are capable of invading solid tumors, and a higher number of tumor-infiltrating NK cells are associated with better survival [19, 20]
Hypoxia is one such factor in the tumor microenvironment (TME) that has been shown to modulate the functions of immune cells through expression of HIF-1α [21,22,23]
Summary
Natural killer cells (NK), the major innate effector cells, with their broad cytotoxicity against tumors are ideal candidates for immunotherapy [1, 2]. On encountering a tumor cell, the NK cell’s ability to kill is determined by the integration of signals from activating and inhibitory receptors expressed on their surface [1]. In addition to expression of ligands to these receptors on tumor cells, oxygen deprivation or hypoxia, universally associated with the tumor microenvironment (TME), is a key determinant of the NK cell cytotoxic response. Hypoxia is considered an adverse prognostic factor for solid tumor regression and can be detrimental to antitumor effector immune cell function [3, 4]. NK cells must initiate dynamic mechanisms to adapt to changes in oxygen tension to execute their functions. Adaptations to hypoxia are facilitated by increased expression and stabilization of transcription factor hypoxiainducible factor-1 (HIF-1), which mediates increased transcriptional activation, glycolysis, proliferation, and angiogenesis [9]. The underlying factors in the TME that leads to HIF upregulation in NK cells and the consequence of this
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