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Preventing Surgery-Induced NK Cell Dysfunction Using Anti-TGF-β Immunotherapeutics.

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Postoperative transforming growth factor-beta (TGF-β) impairs Natural Killer (NK) cell function by altering signaling pathways. Blocking TGF-β with immunotherapeutics restores NK cell interferon-gamma (IFNγ) production and activity.

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Area of Science:

  • Immunology
  • Cellular Biology
  • Cancer Research

Background:

  • Postoperative Natural Killer (NK) cell dysfunction, characterized by suppressed cytotoxicity and interferon-gamma (IFNγ) production, is linked to increased patient morbidity and cancer recurrence.
  • Transforming growth factor-beta (TGF-β) is a key regulator of immune cell signaling and may influence NK cell activity following surgery.

Purpose of the Study:

  • To investigate the hypothesis that elevated postoperative TGF-β levels disrupt NK cell signaling pathways, leading to impaired IFNγ production.
  • To assess the potential of TGF-β blocking agents to restore NK cell function in the postoperative setting.

Main Methods:

  • Peripheral blood mononuclear cells (PBMCs) from cancer surgery patients were analyzed for NK cell receptor expression, downstream signaling, and IFNγ production.
  • In vitro experiments involved incubating healthy NK cells with postoperative plasma or recombinant TGF-β1, with or without TGF-β blocking agents (monoclonal antibody or small molecule inhibitor).
  • Single-cell RNA sequencing was performed on patient PBMCs to analyze gene expression changes.

Main Results:

  • Postoperative day 1 (POD1) showed significantly reduced intracellular IFNγ, activating receptor phosphorylation, and downstream signaling targets (STAT5, STAT4, p38 MAPK, S6) in NK cells.
  • Incubation with recombinant TGF-β1 or POD1 plasma mimicked this NK cell dysfunction, which was reversed by anti-TGF-β immunotherapeutics.
  • Gene expression analysis revealed altered levels of key signaling molecules (S6, FKBP12, Shp-2) and reduced NK cell metabolism transcripts on POD1.
  • Increased pSmad2/3 and decreased pS6 phosphorylation in response to TGF-β1 were observed, and these changes were abrogated by TGF-β blockade.

Conclusions:

  • Postoperative TGF-β signaling, acting through both canonical and mTOR pathways, mediates phenotypic changes that impair NK cell function.
  • Targeting TGF-β represents a promising therapeutic strategy to restore NK cell immunity in the postoperative period, potentially reducing cancer recurrence and improving patient outcomes.