GSK-3α Inhibition in Drug-Resistant CML Cells Promotes Susceptibility to NK Cell-Mediated Lysis in an NKG2D- and
Nayoung Kim1,2, Mi Yeon Kim3, Woo Seon Choi3,4
1Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul 05505, Korea.
Abstract:
Natural killer (NK) cells are innate cytotoxic lymphocytes that provide early protection against cancer. NK cell cytotoxicity against cancer cells is triggered by multiple activating receptors that recognize specific ligands expressed on target cells. We previously demonstrated that glycogen synthase kinase (GSK)-3β, but not GSK-3α, is a negative regulator of NK cell functions via diverse activating receptors, including NKG2D and NKp30. However, the role of GSK-3 isoforms in the regulation of specific ligands on target cells is poorly understood, which remains a challenge limiting GSK-3 targeting for NK cell-based therapy. Here, we demonstrate that GSK-3α rather than GSK-3β is the primary isoform restraining the expression of NKG2D ligands, particularly ULBP2/5/6, on tumor cells, thereby regulating their susceptibility to NK cells. GSK-3α also regulated the expression of the NKp30 ligand B7-H6, but not the DNAM-1 ligands PVR or nectin-2. This regulation occurred independently of BCR-ABL1 mutation that confers tyrosine kinase inhibitor (TKI) resistance. Mechanistically, an increase in PI3K/Akt signaling in concert with c-Myc was required for ligand upregulation in response to GSK-3α inhibition. Importantly, GSK-3α inhibition improved cancer surveillance by human NK cells in vivo. Collectively, our results highlight the distinct role of GSK-3 isoforms in the regulation of NK cell reactivity against target cells and suggest that GSK-3α modulation could be used to enhance tumor cell susceptibility to NK cells in an NKG2D- and NKp30-dependent manner.
Insights
Glycogen synthase kinase-3α (GSK-3α) restrains natural killer (NK) cell targeting of cancer by regulating ligand expression. Inhibiting GSK-3α enhances NK cell cancer surveillance, offering a novel therapeutic strategy.
Area of Science:
- Immunology
- Cell Biology
- Cancer Research
Background:
- Natural killer (NK) cells are crucial for early cancer defense.
- NK cell activity relies on activating receptors recognizing ligands on tumor cells.
- Glycogen synthase kinase-3β (GSK-3β) inhibits NK cell function, but GSK-3 isoform roles in ligand regulation are unclear.
Purpose of the Study:
- To investigate the distinct roles of GSK-3α and GSK-3β isoforms in regulating NK cell target ligands.
- To understand the mechanisms underlying GSK-3 isoform-mediated regulation of tumor cell susceptibility to NK cells.
- To evaluate the therapeutic potential of targeting GSK-3 isoforms for enhancing NK cell-based cancer therapy.
Main Methods:
- Analysis of GSK-3 isoform-specific regulation of NKG2D, NKp30, and DNAM-1 ligands on tumor cells.
- Investigation of signaling pathways (PI3K/Akt, c-Myc) involved in GSK-3α inhibition-induced ligand upregulation.
- In vivo assessment of GSK-3α inhibition's effect on human NK cell-mediated cancer surveillance.
Main Results:
- GSK-3α, not GSK-3β, primarily inhibits the expression of NKG2D ligands (ULBP2/5/6) and NKp30 ligand (B7-H6) on tumor cells.
- GSK-3α inhibition upregulates these ligands, increasing tumor cell susceptibility to NK cells, independently of BCR-ABL1 mutation.
- PI3K/Akt signaling and c-Myc are essential for ligand upregulation following GSK-3α inhibition.
- GSK-3α inhibition significantly enhances human NK cell cancer surveillance in vivo.
Conclusions:
- GSK-3α plays a distinct, inhibitory role in regulating tumor cell ligands recognized by NK cells.
- Targeting GSK-3α can enhance NK cell-mediated cancer immunity through NKG2D and NKp30 pathways.
- GSK-3α inhibition represents a promising strategy to improve NK cell-based cancer therapies.
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