Metformin promotes antitumor activity of NK cells via overexpression of miRNA-150 and miRNA-155.

OBJECTIVES: Metformin, an oral anti-diabetic drug, is known to possess a powerful antitumor effect by modulating the tumor-immune interaction. The precise influence of metformin on natural killer (NK) cells, a crucial innate immunity player, is not completely understood. In our study, analyses of the effect of metformin on the NK cell functional phenotype were performed, and the potential mechanisms underlying it were investigated. METHODS: BALB/C wild type mice were treated with metformin, and the functional phenotype of splenocytes and potential underlying mechanisms were investigated. RESULTS: Metformin significantly boosts NK cell cytotoxicity and the percentage of NKp46+, FasL+, and interferon (IFN)-γ+ NK cells while decreasing interleukin (IL)-10 producing NK cells. Our research also demonstrated that the simultaneous administration of metformin and 1-methyl-DL-tryptophan (1-MT), a specific inhibitor of indoleamine 2,3-dioxygenase (IDO), significantly increased the NK cells synthesis of IFN-γ, IL-17, perforin, and FasL and NKp46 expression. These findings imply that metformin potentiates NK cell cytotoxicity through mechanisms other than IDO blockade. Metformin administration strongly increased the expression of immunostimulatory microRNA (miRNA)-150 and miRNA-155, while decreasing the expression of immunosuppressive miRNA-146a. CONCLUSIONS: These findings suggest that metformin can directly potentiate NK cell activation and cytotoxicity. This research may contribute to dissecting key mechanisms of metformin exerting antitumor activity to advance the use of metformin as an antitumor agent.

Dual blockage of PD-L/PD-1 and IL33/ST2 axes slows tumor growth and improves antitumor immunity by boosting NK cells.

AIMS: Although separate blockage of either IL33/ST2 or PD-L/PD-1 axes has been shown to be beneficial in many tumors, co-blockage of IL33/ST2 and PD-L/PD-1 hasn't been studied yet. MAIN METHODS: 4T1 breast cancer and CT26 colon cancer were inducted in BALB/C wild type (WT) and BALB/C ST2 knockout mice, after which mice underwent anti PD-1 and anti IL-33 treatment. KEY FINDINGS: Co-blockage of IL33/ST2 and PD-L/PD-1 delayed tumor appearance and slowed tumor growth. Enhanced NK cell cytotoxicity against 4T1 tumor cells in ST2 knockout anti-PD-1 treated mice was associated with overexpression of miRNA-150 and miRNA-155, upregulation of NFκB and STAT3, increased expression of activation markers and decreased expression of immunosuppressive markers in splenic and primary tumor derived NK cells. NK cells from ST2 knockout anti-PD-1 treated mice tend to proliferate more and are less prone to apoptosis. Accumulation of immunosuppressive myeloid derived suppressor cells and regulatory T cells was significantly impaired in spleen and primary tumor of ST2 knockout anti-PD-1 treated mice. SIGNIFICANCE: Co-blockage of IL3/ST2 and PD-L/PD-1 axes impedes tumor progression more efficiently than single blockage of either axes, thus offering potential new approach to immunotherapy of tumors.

Elevations in soluble CD40 ligand in patients with high platelet aggregability undergoing percutaneous coronary intervention.

High aggregatory responses despite antiplatelet treatment is associated with an increased risk of thrombotic complications following percutaneous coronary intervention (PCI). In the present study, we investigated the relationship between platelet aggregatory responses to ADP and the release of CD40L (sCD40L): an immunomodulatory compound involved in atherothrombosis - in patients undergoing PCI. ADP-induced platelet aggregation, sCD40L and soluble P-selectin (sP-selectin) were determined before and 24 h after PCI, in samples from 52 patients receiving aspirin and thienopyridines. Platelet aggregation to ADP above the median was defined as 'high aggregation', and aggregation below the median as 'low aggregation'. Data below are medians and interquartile ranges. Patients with 'high platelet aggregability' had a significantly higher increase in both sCD40L (Delta-values: 0.78 (-0.19-3.18) vs. -0.65 (-2.10-0.00) ng/ml, P = 0.002) and sP-selectin (Delta-values: 8.0 (-2.00-16.00) vs. 4.50 (-13.00-0.50) ng/ml, P = 0.001) compared with patients with 'low platelet aggregability'. In a multivariate linear regression analysis adjusted for clinical characteristics and type of preintervention therapy, the only independent predictors of sCD40L and sP-selectin were platelet aggregation to ADP before PCI (P < 0.001) and the combination of platelet aggregation to ADP before PCI and urgency of PCI (P < 0.001). Circulating CD40L is more markedly increased after PCI in patients with high ADP-induced platelet aggregation.