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IRX-2, a novel immunotherapeutic, enhances and protects NK-cell functions in cancer patients.

ABSTRACT: IRX-2 is a primary biologic which has been used for the therapy of head and neck squamous cell cancer (HNSCC) with promising clinical results. Since NK-cell function is compromised in HNSCC patients, we tested the effects of IRX-2 on the restoration of human NK-cell functions in vitro.Peripheral blood mononuclear cells (PBMC) were isolated from 23 HNSCC patients and 10 normal controls (NC). The NK-cell phenotype and functions were compared before and after culture ± IRX-2 or ± 50 IU/ml rhIL-2. Flow cytometry was used to study the NK-cell phenotype, cytotoxic activity and cytokine expression.Impaired NK-cell cytotoxicity in HNSCC patients was related to lower expression of NKG2D, NKp30 and NKp46 receptors (P < 0.05) and not to a decreased frequency of NK cells. Incubation of patients' NK cells with IRX-2 up-regulated the percentage of receptor-positive NK cells (P < 0.05). It also up-regulated cytotoxicity of patients' NK cells (P < 0.01) more effectively than rhIL-2 (P < 0.01). IRX-2, but not rhIL-2, protected NK cells from suppression mediated by TGF-?, and it restored (P < 0.05) expression of activating NK-cell receptors and NK-cell cytotoxicity suppressed by TGF-?. Expression of pSMAD was decreased in NK cells treated with IRX-2 but not in those treated with rhIL-2.IRX-2 was more effective than IL-2 in enhancing NK-cell cytotoxicity and protecting NK-cell function of HNSCC patients in vitro, emphasizing the potential advantage of IRX-2 as a component of future therapies for HNSCC.

SUBMITTER: Schilling B

PROVIDER: S-EPMC3721346 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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IRX-2, a novel immunotherapeutic, enhances and protects NK-cell functions in cancer patients.

Schilling B B Halstead E S ES Schuler P P Harasymczuk M M Egan J E JE Whiteside T L TL

Cancer immunology, immunotherapy : CII 20120120 9

<h4>Background</h4>IRX-2 is a primary biologic which has been used for the therapy of head and neck squamous cell cancer (HNSCC) with promising clinical results. Since NK-cell function is compromised in HNSCC patients, we tested the effects of IRX-2 on the restoration of human NK-cell functions in vitro.<h4>Methods</h4>Peripheral blood mononuclear cells (PBMC) were isolated from 23 HNSCC patients and 10 normal controls (NC). The NK-cell phenotype and functions were compared before and after cult ...[more]

PMID: 22270713

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Project description:Natural killer (NK) cells are an important component in the control of influenza virus infection, acting to both clear virus-infected cells and release antiviral cytokines. Engagement of CD16 on NK cells by antibody-coated influenza virus-infected cells results in antibody-dependent cellular cytotoxicity (ADCC). Increasing the potency of antibody-mediated NK cell activity could ultimately lead to improved control of influenza virus infection. To understand if NK cells can be functionally enhanced following exposure to influenza virus-infected cells, we cocultured human peripheral blood mononuclear cells (PBMCs) with influenza virus-infected human alveolar epithelial (A549) cells and evaluated the capacity of NK cells to mediate antibody-dependent functions. Preincubation of PBMCs with influenza virus-infected cells markedly enhanced the ability of NK cells to respond to immune complexes containing hemagglutinin (HA) and anti-HA antibodies or transformed allogeneic cells in the presence or absence of a therapeutic monoclonal antibody. Cytokine multiplex, RNA sequencing, supernatant transfer, Transwell, and cytokine-blocking/cytokine supplementation experiments showed that type I interferons released from PBMCs were primarily responsible for the influenza virus-induced enhancement of antibody-mediated NK cell functions. Importantly, the influenza virus-mediated increase in antibody-dependent NK cell functionality was mimicked by the type I interferon agonist poly(I·C). We conclude that the type I interferon secretion induced by influenza virus infection enhances the capacity of NK cells to mediate ADCC and that this pathway could be manipulated to alter the potency of anti-influenza virus therapies and vaccines.IMPORTANCE Protection from severe influenza may be assisted by antibodies that engage NK cells to kill infected cells through ADCC. Studies have primarily focused on antibodies that have ADCC activity, rather than the capacity of NK cells to become activated and mediate ADCC during an influenza virus infection. We found that type I interferon released in response to influenza virus infection primes NK cells to become highly reactive to anti-influenza virus ADCC antibodies. Enhancing the capacity of NK cells to mediate ADCC could assist in controlling influenza virus infections.

Project description:NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1-6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12-US21; a genetic arrangement, which is suggestive of an 'accordion' expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family.

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IRX-2, a novel immunotherapeutic, enhances and protects NK-cell functions in cancer patients.

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IRX-2, a novel immunotherapeutic, enhances and protects NK-cell functions in cancer patients.

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