An IL-15 superagonist/IL-15Rα fusion complex protects and rescues NK cell-cytotoxic function from TGF-β1-mediated immunosuppression

Abstract

Natural killer (NK) cells are innate cytotoxic lymphocytes that play a fundamental role in the immunosurveillance of cancers. NK cells of cancer patients exhibit impaired function mediated by immunosuppressive factors released from the tumor microenvironment (TME), such as transforming growth factor (TGF)-β1. An interleukin (IL)-15 superagonist/IL-15 receptor α fusion complex (IL-15SA/IL-15RA; ALT-803) activates the IL-15 receptor on CD8 T cells and NK cells, and has shown significant anti-tumor activity in several in vivo studies. This in vitro study investigated the efficacy of IL-15SA/IL-15RA on TGF-β1-induced suppression of NK cell-cytotoxic function. IL-15SA/IL-15RA inhibited TGF-β1 from decreasing NK cell lysis of four of four tumor cell lines (H460, LNCap, MCF7, MDA-MB-231). IL-15SA/IL-15RA rescued healthy donor and cancer patient NK cell-cytotoxicity, which had previously been suppressed by culture with TGF-β1. TGF-β1 downregulated expression of NK cell-activating markers and cytotoxic granules, such as CD226, NKG2D, NKp30, granzyme B, and perforin. Smad2/3 signaling was responsible for this TGF-β1-induced downregulation of NK cell-activating markers and cytotoxic granules. IL-15SA/IL-15RA blocked Smad2/3-induced transcription, resulting in the rescue of NK cell-cytotoxic function from TGF-β1-induced suppression. These findings suggest that in addition to increasing NK cell function via promoting the IL-15 signaling pathway, IL-15SA/IL-15RA can function as an inhibitor of TGF-β1 signaling, providing a potential remedy for NK cell dysfunction in the immunosuppressive tumor microenvironment.

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Correction to: Total analysis of clinical factors for surgical success of adenotonsillectomy in pediatric OSAS

Abstract

The authors would like to publish this erratum to indicate Dr Rayleigh Ping-Ying Chiang as the corresponding author of this article.

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Impacted and transmigrated mandibular canines: an analysis of 3D radiographic imaging data

Abstract

Objectives

Impacted and transmigrated mandibular canines differ greatly in incidence, etiopathology, associated anomalies, and treatment prospects, when compared to their maxillary counterparts. The aim of this study was to provide a detailed analysis of 3D radiographic imaging data of impacted mandibular canines.

Materials and methods

In a retrospective cross-sectional study, CT/CBCT data of 88 patients with a total of 94 impacted mandibular canines were analysed. Evaluated parameters included location, morphology, neighbouring structures, associated anomalies, the influence of those factors on mandibular canine transmigration, as well as applied treatment.

Results

Transmigration was found to occur in 40.4% of impacted mandibular canines. Transmigrated canines were located significantly more basally and horizontally angulated. Further, transmigration was significantly associated with a lack of contact to adjacent teeth and the canine's apex not contacting the mandibular cortical bone. The overall incidence of root resorptions of adjacent teeth related to impacted mandibular canines was 7.3% and was more likely, if the canine was lingually impacted. While about half of the non-transmigrated impacted canines were orthodontically aligned, half of the transmigrated canines were surgically removed. Monitoring was the second most applied treatment strategy for both groups, and no canines were autotransplantated.

Conclusions

Root resorption of adjacent teeth and transmigration are commonly occurring phenomena related to impacted mandibular canines.

Clinical relevance

Treatment often entails the surgical removal of the canine—especially in cases of transmigration. The findings emphasise the importance of early diagnosis and CT/CBCT imaging for further diagnostics and future research of impacted mandibular canines.

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Biomarkers and asthma management: analysis and potential applications

Purpose of review Asthma features a high degree of heterogeneity in both pathophysiology and therapeutic response, resulting in many asthma patients being treated inadequately. Biomarkers indicative of underlying pathological processes could be used to identify disease subtypes, determine prognosis and to predict or monitor treatment response. However, the newly identified as well as more established biomarkers have different applications and limitations. Recent findings Conventional markers for type 2-high asthma, such as blood eosinophils, fraction of exhaled nitric oxide, serum IgE and periostin, feature limited sensitivity and specificity despite their significant correlations. More distinctive models have been developed by combining biomarkers and/or using omics techniques. Recently, a model with a positive predictive value of 100% for identification of type 2-high asthma based on a combination of minimally invasive biomarkers was developed. Summary Individualisation of asthma treatment regimens on the basis of biomarkers is necessary to improve asthma control. However, the suboptimal properties of currently available conventional biomarkers limit its clinical utility. Newly identified biomarkers and models based on combinations and/or omics analysis must be validated and standardised before they can be routinely applied in clinical practice. The development of robust biomarkers will allow development of more efficacious precision medicine-based treatment approaches for asthma. Correspondence to Anke H. Maitland-van der Zee, Department of Respiratory Medicine, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel: +31 20 566 4356; e-mail: a.h.maitland@amc.nl Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Role of epigenetics in the development of childhood asthma

Purpose of review Epigenetic marks are emerging as mediators of genetics and the environment on complex disease phenotypes, including childhood asthma and allergy. Recent findings Epigenome-wide association studies over the past year have added to the growing body of evidence supporting significant associations of epigenetic regulation of gene expression and asthma and allergy. Studies in children have identified signatures of eosinophils in peripheral blood, Th2 cell transcription factors and cytokines in peripheral blood mononuclear cells, and epithelial dysfunction in the respiratory epithelium. Importantly, studies at birth have begun to decipher the contribution of epigenetic marks to asthma inception. Few studies have also begun to address the contribution of genetics and the environment to these associations. Summary Next generation of epigenome-wide association studies that will deal with confounders, study the influence of the genetics and environment, and incorporate multiple datasets to provide better interpretation of the findings are on the horizon. Identification of key epigenetic marks that are shaped by genetics and the environment, and impact transcription of specific genes will help us have a better understanding of etiology, heterogeneity and severity of asthma, and will also empower us to develop biologically driven therapeutics and biomarkers for secondary prevention of this disease. Correspondence to Ivana V. Yang, University of Colorado Denver 12700 East 19th Avenue, 8611 Aurora, CO 80045. E-mail: ivana.yang@ucdenver.edu Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Development of allergic sensitization and its relevance to paediatric asthma

Purpose of review The purpose of this review is to summarize the recent evidence on the distinct atopic phenotypes and their relationship with childhood asthma. We start by considering definitions and phenotypic classification of atopy and then review evidence on its association with asthma in children. Recent findings It is now well recognized that both asthma and atopy are complex entities encompassing various different sub-groups that also differ in the way they interconnect. The lack of gold standards for diagnostic markers of atopy and asthma further adds to the existing complexity over diagnostic accuracy and definitions. Although recent statistical phenotyping studies contributed significantly to our understanding of these heterogeneous disorders, translating these findings into meaningful information and effective therapies requires further work on understanding underpinning biological mechanisms. Summary The disaggregation of allergic sensitization may help predict how the allergic disease is likely to progress. One of the important questions is how best to incorporate tests for the assessment of allergic sensitization into diagnostic algorithms for asthma, both in terms of confirming asthma diagnosis, and the assessment of future risk. Correspondence to Adnan Custovic, MD, PhD, Department of Paediatrics, Imperial College London, St Mary's Campus Medical School, Room 244, Norfolk Place, London W2 1PG, UK. Tel: +44 20 7594 3274; fax: +44 20 7594 3984; e-mail: a.custovic@imperial.ac.uk Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Assessing the impact of air pollution on childhood asthma morbidity: how, when, and what to do

Purpose of review Exposure to air pollutants is linked with poor asthma control in children and represents a potentially modifiable risk factor for impaired lung function, rescue medication use, and increased asthma-related healthcare utilization. Identification of the most relevant pollutants to asthma as well as susceptibility factors and strategies to reduce exposure are needed to improve child health. Recent findings The current available literature supports the association between pollutants and negative asthma outcomes. Ethnicity, socioeconomic status, and presence of certain gene polymorphisms may impact susceptibility to the negative health effects of air pollution. Improved air quality standards were associated with better asthma outcomes. Summary The link between air pollution and pediatric asthma morbidity is supported by the recent relevant literature. Continued efforts are needed to identify the most vulnerable populations and develop strategies to reduce exposures and improve air quality. Correspondence to Allison J. Burbank, MD, Department of Pediatrics, Division of Allergy, Immunology, & Rheumatology, 104 Mason Farm Road, CB #7310, Chapel Hill, NC 27599-7310, USA. Tel: +1 919 843 2714; fax: +1 919 962 4421; e-mail: allison_burbank@med.unc.edu Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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