The transcriptome of lung tumor-infiltrating dendritic cells reveals a tumor-supporting phenotype and a microRNA signature with negative impact on clinical outcome

Targeting immunomodulatory pathways has ushered a new era in lung cancer therapy. Further progress requires deeper insights into the biology of immune cells in the lung cancer micro-environment. Dendritic cells (DCs) represent a heterogeneous and highly plastic immune cell system with a central role in controlling immune responses. The intratumoral infiltration and activation status of DCs are emerging as clinically relevant parameters in lung cancer. In this study, we used an orthotopic preclinical model of lung cancer to dissect how the lung tumor micro-environment affects tissue-resident DCs and extract novel biologically and clinically relevant information. Lung tumor-infiltrating leukocytes expressing generic DC markers were found to predominantly consist of CD11b(+) cells that, compare with peritumoral lung DC counterparts, strongly overexpress the T-cell inhibitory molecule PD-L1 and acquire classical surface markers of tumor-associated macrophages (TAMs). Transcriptome analysis of these CD11b(+) tumor-infiltrating DCs (TIDCs) indicates impaired antitumoral immunogenicity, confirms the skewing toward TAM-related features, and indicates exposure to a hypoxic environment. In parallel, TIDCs display a specific microRNA (miRNA) signature dominated by the prototypical lung cancer oncomir miR-31. In vitro, hypoxia drives intrinsic miR-31 expression in CD11b(+) DCs. Conditioned medium of miR-31 overexpressing CD11b(+) DCs induces pro-invasive lung cancer cell shape changes and is enriched with pro-metastatic soluble factors. Finally, analysis of TCGA datasets reveals that the TIDC-associated miRNA signature has a negative prognostic impact in non-small cell lung cancer. Together, these data suggest a novel mechanism through which the lung cancer micro-environment exploits the plasticity of the DC system to support tumoral progression

The transcriptome of lung tumor-infiltrating dendritic cells reveals a tumor-supporting phenotype and a microRNA signature with negative impact on clinical outcome

Targeting immunomodulatory pathways has ushered a new era in lung cancer therapy. Further progress requires deeper insights into the biology of immune cells in th

Lung tumours reprogram pulmonary dendritic cell immunogenicity at the microRNA level

Lung cancer arises in a context of tumour-induced immune suppression. Dendritic cells (DCs) are central players in the induction of anti-tumoural immunity, providing critical signals that drive the induction of cytotoxic T-cell responses. Meanwhile, microRNAs are associated with tumour development as well as immune regulation. We postulated that lung tumours escape immune control by reprogramming DC immunogenicity at the microRNA level. Using an orthotopic model of lung cancer, we first identified the DC population responsible for transport and cross-presentation of lung tumour-derived antigens to naive T cells in the draining mediastinal lymph nodes (LNs). Profiling the full microRNA repertoire of these DCs revealed a restricted set of microRNAs that was consistently dysregulated in the presence of lung tumours, with miR-301a as one of the top upregulated transcripts. Overexpression of miR-301a in DCs suppressed IL-12 secretion, decreased IFN-gamma release from antigen-specific cytotoxic T cells, and shifted antigen-specific T helper cytokine profile away from IFN-gamma towards IL-13 and IL-17A-secreting T cells. Strikingly, DC-selective Dicer1 gene deletion resulted in delayed lung tumour growth and a survival benefit. Taken together, our data reveal that lung tumours induce an immunosuppressive microRNA signature in pulmonary DCs. Interfering with the DC-intrinsic capacity to remodel microRNA repertoires affects lung tumour outcome

Benchmarking adult CT-dose levels to regional and national references using a dose-tracking software: a multicentre experience

Abstract Objectives To benchmark CT-dose data for standard adult CT studies to regional and national reference levels using a dose-tracking system. Methods Data from five CT systems from three hospitals were collected over a 1- to 2.5-year period (2012–2014), using the same type of dose management system. Inclusion criteria were adult patients and standard CT-head, CT-abdomen-pelvis, CT-thorax, CT-lumbar spine, CT-pulmonary embolism, CT-cervical spine and CT-thorax-abdomen studies, with one helical scan. Volumetric CT-dose index (CTDIvol), dose length product (DLP) and scan length from 31,709 scans were analysed statistically. Results After dose optimisation CTDIvol and DLP values were below the national diagnostic reference levels (DRLs) for all CT studies and for all systems investigated. Mostly no significant differences were found between CTDIvol and DLP levels (p values ≥ 0.01) of CT studies performed on different scanners within the same hospital. Significant dose differences (p values < 0.01) were instead observed among hospitals for comparable CT studies. Dose level range and scan length differences for similar CT studies were revealed. Conclusions Dose-tracking systems help to reduce CT-dose levels below national DRLs. However, dose and protocol data comparison between and within hospitals has the potential to further reduce variability in dose data of standard adult CT studies. Key Points • Retrospective three-centre study on dose levels of standard adult CT procedures. • Dose-tracking systems help hospitals to stay below national dose reference levels. • Dose-tracking systems help to align CT dose levels between scanners within hospitals. • Benchmarking shows CT dose level variability for similar examinations in different hospitals. • Differences in dose level range/scan length for similar CT studies are revealed

Multicenter randomized controlled trial of vitamin K antagonist replacement by rivaroxaban with or without vitamin K2 in hemodialysis patients with atrial fibrillation : the Valkyrie study

Background: Vitamin K antagonists (VKAs), although commonly used to reduce thromboembolic risk in atrial fibrillation, have been incriminated as probable cause of accelerated vascular calcification (VC) in patients on hemodialysis. Functional vitamin K deficiency may further contribute to their susceptibility for VC. We investigated the effect of vitamin K status on VC progression in 132 patients on hemodialysis with atrial fibrillation treated with VKAs or qualifying for anticoagulation. Methods: Patients were randomized to VKAs with target IN R 2-3, rivaroxaban 10 mg daily, or rivaroxaban 10 mg daily plus vitamin K2 2000 mu g thrice weekly during 18 months. Systemic dp-ucMGP levels were quantified to assess vascular vitamin K status. Cardiac and thoracic aorta calcium scores and pulse wave velocity were measured to evaluate VC progression. Results: Baseline dp-ucMGP was severely elevated in all groups. Initiation or continuation of VKAs further increased dp-ucMGP, whereas levels decreased in the rivaroxaban group and to a larger extent in the rivaroxaban+vitamin K2 group, but remained nevertheless elevated. Changes in coronary artery, thoracic aorta, and cardiac valve calcium scores and pulse wave velocity were not significantly different among the treatment arms. All cause death, stroke, and cardiovascular event rates were similar between the groups. Bleeding outcomes were not significantly different, except for a lower number of life-threatening and major bleeding episodes in the rivaroxaban arms versus the VKA arm. Conclusions: Withdrawal of VKAs and high-dose vitamin K2 improve vitamin K status in patients on hemodialysis, but have no significant favorable effect on VC progression. Severe bleeding complications may be lower with rivaroxaban than with VKAs