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GSK3 Inhibition Drives Maturation of NK Cells and Enhances Their Antitumor Activity

Frank Cichocki1, Bahram Valamehr2, Ryan Bjordahl2

  • 1Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Cancer Center, Minneapolis, Minnesota.

Cancer Research
|August 10, 2017
PubMed

Insights

Inhibiting GSK3 kinase enhances natural killer (NK) cell maturation, boosting their cancer-fighting abilities. This approach improves NK cell cytotoxicity and tumor control, offering a promising avenue for cancer immunotherapy.

Area of Science:

  • Immunology
  • Cell Biology
  • Cancer Research

Background:

  • Natural Killer (NK) cell maturation, marked by CD57 expression, correlates with enhanced cytotoxic activity and cytokine production (TNF, IFNγ).
  • CD57+ NK cells play a crucial role in cancer immunosurveillance, but mechanisms driving their maturation remain largely unknown.

Purpose of the Study:

  • To investigate the effect of GSK3 kinase inhibition on human NK cell maturation.
  • To evaluate the impact of GSK3 inhibition on NK cell function and anti-cancer efficacy.

Main Methods:

  • Human peripheral blood NK cells were expanded ex vivo with IL15 and treated with a GSK3 inhibitor.
  • NK cell maturation markers (CD57, T-BET, ZEB2, BLIMP-1), viability, proliferation, and cytotoxic functions were assessed.
  • In vivo efficacy was tested using a mouse xenograft model of ovarian cancer.

Main Results:

  • GSK3 inhibition significantly upregulated CD57 expression and key transcription factors (T-BET, ZEB2, BLIMP-1) without affecting NK cell viability or proliferation.
  • Ex vivo expanded NK cells treated with GSK3 inhibitor showed enhanced TNF and IFNγ production, natural cytotoxicity, and antibody-dependent cellular cytotoxicity (ADCC).
  • Adoptive transfer of GSK3 inhibitor-conditioned NK cells resulted in more robust and durable control of ovarian tumors in a mouse model.

Conclusions:

  • Pharmacologic inhibition of GSK3 kinase is a potent strategy to promote late-stage maturation of human NK cells.
  • GSK3 inhibition enhances NK cell effector functions critical for cancer immunotherapy.
  • Conditioned NK cells demonstrate improved anti-tumor activity in vivo, highlighting their therapeutic potential.

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