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Suppression of natural killer-cell and dendritic-cell apoptotic tumoricidal activity in patients with head and neck cancer.

ABSTRACT: Natural killer (NK) cells and dendritic cells (DCs) mediate tumor cell apoptosis using tumor necrosis factor superfamily ligands (TNFSFLs). This cytotoxicity is an important anticancer immune defense mechanism.We examined TNFSFL expression and apoptotic tumoricidal activity (ATA) of purified NK cells and DCs, and peripheral blood mononuclear leukocytes (PBMLs) of healthy individuals and patients with head and neck cancer (HNC) before and after cancer ablation.PBMLs, NK cells and DCs, but not NK-cell/DC-depleted PBMLs, expressed multiple TNFSFLs and mediated ATA. Both TNFSFL expression and ATA were suppressed in tumor-bearing, and restored in tumor-ablated patients with (HNC) Soluble TNF superfamily receptors (solTNFSFRs) were increasingly bound by PBNLs of tumor-bearing HNC patients. Dissociation of solTNFSFR led to more pronounced increases in TNFSFL expression and ATA of PBMLs of patients with HNC than healthy individuals.NK-cell and DC TNFSFL expression and ATA are suppressed in patients with HNC. This suppression is tumor-dependent and possibly mediated by solTNFSFRs.

SUBMITTER: Baskic D

PROVIDER: S-EPMC3721337 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Suppression of natural killer-cell and dendritic-cell apoptotic tumoricidal activity in patients with head and neck cancer.

Baskic Dejan D Vujanovic Lazar L Arsenijevic Nebojsa N Whiteside Theresa L TL Myers Eugene N EN Vujanovic Nikola L NL

Head & neck 20120405 3

<h4>Background</h4>Natural killer (NK) cells and dendritic cells (DCs) mediate tumor cell apoptosis using tumor necrosis factor superfamily ligands (TNFSFLs). This cytotoxicity is an important anticancer immune defense mechanism.<h4>Methods</h4>We examined TNFSFL expression and apoptotic tumoricidal activity (ATA) of purified NK cells and DCs, and peripheral blood mononuclear leukocytes (PBMLs) of healthy individuals and patients with head and neck cancer (HNC) before and after cancer ablation.< ...[more]

PMID: 22488918

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Project description:BackgroundMetformin slows tumor growth and progression in vitro, and in combination with chemoradiotherapy, resulted in high overall survival in patients with head and neck cancer squamous cell carcinoma (HNSCC) in our phase 1 clinical trial (NCT02325401). Metformin is also postulated to activate an antitumor immune response. Here, we investigate immunologic effects of metformin on natural killer (NK) and natural killer T cells, including results from two phase I open-label studies in patients with HNSCC treated with metformin (NCT02325401, NCT02083692).MethodsPeripheral blood was collected before and after metformin treatment or from newly diagnosed patients with HNSCC. Peripheral immune cell phenotypes were evaluated using flow cytometry, cytokine expression by ELISA and/or IsoLight, and NK cell-mediated cytotoxicity was determined with a flow-based NK cell cytotoxicity assay (NKCA). Patient tumor immune infiltration before and after metformin treatment was analyzed with immunofluorescence. NK cells were treated with either vehicle or metformin and analyzed by RNA sequencing (RNA-seq). NK cells were then treated with inhibitors of significant pathways determined by RNA-seq and analyzed by NKCA, ELISA, and western blot analyses.ResultsIncreased peripheral NK cell activated populations were observed in patients treated with metformin. NK cell tumor infiltration was enhanced in patients with HNSCC treated with metformin preoperatively. Metformin increased antitumorigenic cytokines ex vivo, including significant increases in perforin. Metformin increased HNSCC NK cell cytotoxicity and inhibited the CXCL1 pathway while stimulating the STAT1 pathway within HNSCC NK cells. Exogenous CXCL1 prevented metformin-enhanced NK cell-mediated cytotoxicity. Metformin-mediated NK cell cytotoxicity was found to be AMP-activated protein kinase independent, but dependent on both mechanistic target of rapamycin and pSTAT1.ConclusionsOur data identifies a new role for metformin-mediated immune antitumorigenic function through NK cell-mediated cytotoxicity and downregulation of CXCL1 in HNSCC. These findings will inform future immunomodulating therapies in HNSCC.

Project description:UNLABELLED:VTX-2337 (USAN: motolimod) is a selective toll-like receptor 8 (TLR8) agonist, which is in clinical development as an immunotherapy for multiple oncology indications, including squamous cell carcinoma of the head and neck (SCCHN). Activation of TLR8 enhances natural killer cell activation, increases antibody-dependent cell-mediated cytotoxicity, and induces Th1 polarizing cytokines. Here, we show that VTX-2337 stimulates the release of mature IL-1? and IL-18 from monocytic cells through coordinated actions on both TLR8 and the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome complex. In vitro, VTX-2337 primed monocytic cells to produce pro-IL-1?, pro-IL-18, and caspase-1, and also activated the NLRP3 inflammasome, thereby mediating the release of mature IL-1? family cytokines. Inhibition of caspase-1 blocked VTX-2337-mediated NLRP3 inflammasome activation, but had little impact on production of other TLR8-induced mediators such as TNF?. IL-18 activated natural killer cells and complemented other stimulatory pathways, including Fc?RIII and NKG2D, resulting in IFN? production and expression of CD107a. NLRP3 activation in vivo was confirmed by a dose-related increase in plasma IL-1? and IL-18 levels in cynomolgus monkeys administered VTX-2337. These results are highly relevant to clinical studies of combination VTX-2337/cetuximab treatment. Cetuximab, a clinically approved, epidermal growth factor receptor-specific monoclonal antibody, activates NK cells through interactions with Fc?RIII and facilitates ADCC of tumor cells. Our preliminary findings from a Phase I open-label, dose-escalation, trial that enrolled 13 patients with recurrent or metastatic SCCHN show that patient NK cells become more responsive to stimulation by NKG2D or Fc?RIII following VTX-2337 treatment. Together, these results indicate that TLR8 stimulation and inflammasome activation by VTX-2337 can complement Fc?RIII engagement and may augment clinical responses in SCCHN patients treated with cetuximab. TRIAL REGISTRATION:ClinicalTrials.gov NCT01334177.

Dataset Information

Suppression of natural killer-cell and dendritic-cell apoptotic tumoricidal activity in patients with head and neck cancer.

Publications

Suppression of natural killer-cell and dendritic-cell apoptotic tumoricidal activity in patients with head and neck cancer.

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