Preventing Surgery-Induced NK Cell Dysfunction Using Anti-TGF-β Immunotherapeutics
Marisa Market1,2, Gayashan Tennakoon1,2, Marlena Scaffidi1,2
1Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H8L6, Canada.
International Journal of Molecular Sciences
|December 11, 2022
Summary
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.
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.
