Hypoxia Impairs NK Cell Cytotoxicity through SHP-1-Mediated Attenuation of STAT3 and ERK Signaling Pathways

Abstract

Natural killer (NK) cells are innate immune effectors with potent antitumor activity. However, tumor cells can create an immunosuppressive microenvironment to escape immune surveillance. Although accumulating evidence indicates that microenvironmental hypoxia plays an important role in favoring tumor development and immune evasion, it remains unclear by what means hypoxia directly impairs NK cell antitumor activity. In this study, we confirmed that hypoxic NK cells showed significantly lower cytotoxicity against tumor cells. Consistent with this finding, we found that the reduction in NK cell cytotoxicity resulting from hypoxia correlated to the lower expression of granzyme B, IFN-γ, and degranulation marker CD107a, as well as activating receptors including NKp30, NKp46, and NKG2D expressed on the surface of NK cells. More importantly, we further demonstrated that a reduction in the phosphorylation levels of ERK and STAT3 secondary to hypoxia was strongly associated with the attenuated NK cell cytotoxicity. Focusing on the mechanism responsible for reduced phosphorylation levels of ERK and STAT3, we reveal that the activation of protein tyrosine phosphatase SHP-1 (Src homology region 2 domain-containing phosphatase-1) following hypoxia might play an essential role in this process. By knocking down SHP-1 or blocking its activity using a specific inhibitor TPI-1, we were able to partially restore NK cell cytotoxicity under hypoxia. Taken together, we demonstrate that hypoxia could impair NK cell cytotoxicity by decreasing the phosphorylation levels of ERK and STAT3 in a SHP-1-dependent manner. Therefore, targeting SHP-1 could provide an approach to enhance NK cell-based tumor immunotherapy.

Optimising NK cell metabolism to increase the efficacy of cancer immunotherapy

“…HIF1α also is an important metabolic regulator under certain normoxic conditions and plays an crucial role in supporting glycolysis and effector function in CD8+ cytotoxic T cells [ 55 ]. However, HIF1α is not a key regulator of NK cell metabolism and the data suggests that HIF1α expression in NK cells can have pro-tumour effects [ 65 , 66 ]. HIF1α-deficient NK cells have normal metabolic and effector function responses following IL2+IL12 cytokine stimulation under normoxic conditions, suggesting HIF1α is dispensable for normal cytokine-induced NK cell responses [ 8 ].…”

Realizing Innate Potential: CAR-NK Cell Therapies for Acute Myeloid Leukemia

“…Expression of NCRs is reduced relative to healthy controls in an effect reliant on NK and blast cell contact [ 85 ]. NKG2D downregulation occurs secondary to chronic exposure to hypoxia, cell surface and soluble NKG2D ligands and via blast and stroma derived TGF-β [ 86 , 87 , 88 ]. NKG2A expression is often increased, at least partially driven by blast cell production of IL-10, while IFN-γ induces expression of the ligand for NKG2A (HLA-E), on blast cells [ 89 , 90 ].…”

“…MDSC populations upregulate CD155 in response to ROS, impairing traditional NK cell but not adaptive NK cell function reflecting differing TIGIT expression [ 106 ]. Finally, hypoxia has been associated with varied inhibitory NK cell effects including reduced activating receptor expression and impaired production of IFN-γ [ 88 , 107 ]. The transcription factor HIF1α is a clinically relevant mediator of hypoxia related NK cell inhibition in cancer [ 108 ].…”

Postoperative Natural Killer Cell Dysfunction: The Prime Suspect in the Case of Metastasis Following Curative Cancer Surgery

“…Hypoxic NK cells also exhibited lower cytotoxicity against FO-1 melanoma cells due to impaired degranulation [ 105 ]. Recent investigations have revealed that hypoxia in NK cells induces the activity of protein tyrosine phosphatase SHP-1 (Src homology region 2 domain-containing phosphatase-1), which attentuates STAT3 and ERK signalling leading to an impairment of NK cell function [ 106 ]. Moreover, tumor cells have evolved to use hypoxic stress to their advantage through HIF activation [ 107 , 108 ], resulting in immune suppression and tolerance to immune surveillance by promoting MDSC accumulation, inhibiting DC maturation, and recruiting T regs , which ultimately impair NK cell function [ 104 , 108 , 109 ].…”