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Canonical TGF-β Signaling Pathway Represses Human NK Cell Metabolism

Vanessa Zaiatz-Bittencourt1, David K Finlay2,3, Clair M Gardiner2

  • 1School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and.

Journal of Immunology (Baltimore, Md. : 1950)
|May 4, 2018
PubMed

Insights

Transforming growth factor-beta (TGF-β) inhibits key metabolic pathways in human natural killer (NK) cells. Inhibiting TGF-β signaling may enhance NK cell metabolism and function for cancer immunotherapy.

Area of Science:

  • Immunology
  • Cell Metabolism
  • Cancer Immunotherapy

Background:

  • Cytokines rapidly alter human natural killer (NK) cell metabolism, enhancing glycolysis and oxidative phosphorylation.
  • The subsequent regulation of these cytokine-induced metabolic changes in NK cells remains largely unknown.

Purpose of the Study:

  • To investigate the regulatory role of transforming growth factor-beta (TGF-β) on human NK cell metabolism.
  • To determine the impact of TGF-β on NK cell metabolic pathways and nutrient receptor expression.
  • To explore the therapeutic potential of targeting TGF-β signaling for enhancing NK cell-based immunotherapies.

Main Methods:

  • Treatment of human NK cells with TGF-β and/or cytokines.
  • Assessment of metabolic parameters including oxidative phosphorylation, glycolytic capacity, and respiratory capacity.
  • Analysis of transferrin receptor CD71 expression.
  • Evaluation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway.
  • Inhibition of the canonical TGF-β signaling pathway.

Main Results:

  • TGF-β significantly inhibited cytokine-induced oxidative phosphorylation, glycolytic capacity, and respiratory capacity in human NK cells.
  • TGF-β suppressed the expression of the nutrient receptor CD71.
  • Unlike in murine NK cells, TGF-β did not inhibit mTORC1 signaling in human NK cells.
  • Inhibition of the canonical TGF-β signaling pathway restored NK cell metabolic and functional responses.

Conclusions:

  • TGF-β acts as a negative regulator of human NK cell metabolism and function.
  • Targeting TGF-β signaling, independent of mTORC1, offers a potential strategy to enhance NK cell metabolic fitness.
  • Pharmacological inhibition of TGF-β may improve NK cell-based cancer immunotherapies by boosting their metabolic and functional capabilities.

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