EBioMedicine最新文献

Background: Tumour associated macrophages (TAMs) and exhausted T cells are dominant in the immuno-suppressive tumour microenvironment (TME) and pose a challenge to effective cancer immunotherapy in solid tumours.

Methods: In this study, we immunised llamas and generated monovalent and biparatopic nanobodies (Nbs) against colony stimulating factor 1 receptor (CSF-1R) and programmed death receptor 1 (PD-1) to re-educate TAMs and overcome T cell exhaustion, respectively, in the TME. To circumvent short systemic half-life and low peak concentrations of Nbs in the TME, we developed a platform of allogenic off-the-shelf stem cells (SC) releasing biparatopic PD-1 and CSF-1R Nbs and tested its efficacy in different mouse models.

Findings: Nbs targeting CSF-1R and PD-1 inhibited the CSF1/CSF-1R and PD-1/PD-L1 pathways, respectively, with biparatopic Nbs demonstrating superior efficacy and functionality compared with their monovalent counterparts. Locoregional SC mediated release of biparatopic CSF-1R and PD-1 Nbs, reduced tumour growth by increasing T cell numbers, enhancing T cell activation, and by shifting the macrophage polarisation towards a pro-inflammatory phenotype. Moreover, the presence of both Nbs improved dendritic cells (DCs) activation within the TME. Finally, we show that biocompatible gel encapsulated SC releasing Nbs against PD-1 and CSF-1R have therapeutic efficacy in a highly immunosuppressive glioblastoma model post-tumour resection.

Interpretation: Taken together, our findings establish a cell-based Nb platform targeting both innate and adaptive immune axis within the TME, which has the potential to facilitate treatment of solid cancers that are otherwise refractory to conventional immunotherapies.

Funding: This study was mainly supported by Institutional Funds (K.S). A part of in vivo Nb characterisation was supported by NIH grant R01-CA285519 (K.S.) and the Nb dye conjugation and modelling was supported by NIH grant R01-AI165666 (M.R).

Background: Benign adrenal tumours, found in 1-7% of adults, can be non-functioning (NFAT) or show mild autonomous cortisol secretion (MACS), i.e., biochemical cortisol excess without manifestations of Cushing's syndrome (CS). MACS occurs in 20-50% of cases and is linked to increased cardiometabolic burden.

Methods: In a cross-sectional study, we analysed the 24-h urinary steroid metabolome of 1305 prospectively recruited patients (649 NFAT, 591 MACS, 65 adrenal CS) by tandem mass spectrometry. A sub-group (104 NFAT, 140 MACS, 47 adrenal CS) underwent untargeted serum metabolome analysis by mass spectrometry. Data were analysed using linear regression and supervised machine learning.

Findings: Alongside the expected increase in glucocorticoid excretion from NFAT over MACS to adrenal CS, steroid analysis revealed decreased classic androgen metabolite excretion. By contrast, adrenal-derived 11-oxygenated androgen metabolites remained unchanged. Both glucocorticoid metabolites and the major 11-oxygenated androgen metabolite 11β-hydroxyandrosterone correlated with a higher risk of hypertension and type 2 diabetes. Untargeted metabolome analysis revealed gradual changes towards a lipotoxic phenotype from NFAT over MACS to adrenal CS, with perturbations in glycerophospholipids, lysoglycerophospholipids, triacylglycerides, ceramides, sphingolipids, and acylcarnitines.

Interpretation: MACS represents a metabolic continuum between NFAT and adrenal CS. Increased activity of the adrenal enzyme 11β-hydroxylase (CYP11B1), which catalyses key steps in cortisol and 11-oxygenated androgen biosynthesis, may contribute to steroid excess and cardiometabolic morbidity in MACS. These findings suggest that CYP11B1 may be a potential therapeutic target to ameliorate metabolic dysfunction in MACS.

Funding: NIHR Birmingham Biomedical Research Centre; Diabetes UK; Wellcome Trust; European Commission; Medical Research Council.

Background: Hunger is commonly linked to negative mood, and mood shifts are believed to arise from sensing the body's internal state. However, it remains unclear whether this link is driven by subconscious effects of circulating glucose levels or by consciously sensed metabolic states. Here, we test whether glucose levels directly influence mood or indirectly via subjective ratings of metabolic state.

Methods: In this observational cohort study, 90 healthy adults (female = 46; male = 44) were continuously monitored throughout the day using interstitial glucose sensors for four weeks while completing ecological momentary assessments up to twice per day (EMA; M = 48 assessments per participant) to rate mood and perceived metabolic states.

Findings: As expected, hungry participants reported lower mood, and metabolic state ratings were associated with glucose levels. Although glucose levels were associated with mood, the metabolic state ratings mediated this association. Individual differences reflecting metabolic health (i.e., BMI and insulin resistance) did not affect the interaction between glucose and metabolic state ratings on mood. Notably, individuals with higher interoceptive accuracy had fewer fluctuations in mood ratings.

Interpretation: We conclude that hunger-related mood shifts depend on conscious sensing of the body's internal state instead of acting subconsciously. Our study highlights the relevance of considering the self-report of bodily signals in understanding mood shifts, offering new fundamental insights into mood regulation mechanisms.

Funding: The study was supported by the German Research Foundation (DFG) grants KR 4555/7-1, KR 4555/9-1, KR 4555/10-1, and DE 2319/22-1.

Background: Long term respiratory symptoms are reported following recovery of acute COVID-19 infection and residual lung abnormalities (RLA) on follow-up thoracic computed tomography (CT) after COVID-19 hospitalisation have been observed. It is unknown whether RLA are associated with epithelial lung injury.

Methods: Plasma was sampled from the observational Post HOSPitalisation-COVID cohort at five months post-hospitalisation. Epithelial injury biomarkers Krebs von den Lungen-6 (KL-6), matrix metalloproteinase 7 (MMP-7), surfactant protein-D (SP-D) and surfactant protein-A (SP-A) were assayed. In those without follow-up CT, RLA at-risk was defined by percent predicted DL_CO <80% and/or abnormal chest X-ray, otherwise they were considered low-risk. Follow-up CT RLA was defined as combined involvement of ground glass opacity and reticulation ≥10%.

Findings: A total of 957 people were included, 846 people with no CT (at-risk n = 103; 12.2%), 111 people with follow-up CT (RLA ≥10% n = 85; 76.6%). All epithelial injury biomarkers were significantly elevated in people at-risk of RLA compared with low-risk. KL-6 and MMP-7 were significantly higher in people with ≥10% RLA than those with <10%, SP-D and SP-A did not reach significance. SP-D and SP-A were associated with percent involvement of reticulation (3.22%, 95% CI 1.19-5.24; 3.03%, 95% CI 0.76-5.30, respectively).

Interpretation: RLA after acute COVID-19 infection were consistent with elevated epithelial injury biomarkers and pro-fibrotic signalling. Future studies should address the temporal association between fibrotic biomarkers and resolution or progression of radiological involvement.

Funding: MRC-UK Research and Innovation and National Institute for Health Research (NIHR) rapid response panel to tackle COVID-19 (MR/V027859/1; COV0319; MR/W006111/1).

Background: The impact of CFTR modulator therapy on host immunity and outcomes in people with Cystic Fibrosis (CF)-related Aspergillus lung disease is poorly defined. We aimed to characterise fungal-relevant clinical outcomes post-CFTR modulators and assess effects on the Aspergillus-dependent Type I/III interferome.

Methods: Biomarkers of Aspergillus-related lung disease (Aspergillus-specific IgE/IgG), anti-fungal and corticosteroid therapy were analysed in a retrospective cohort of people with CF pre and post Elexacaftor/Tezacaftor/Ivacaftor (ETI) modulator therapy. Homozygous F508del (CF) and CFTR TALEN-corrected bronchial epithelial cells (BECs) were challenged with Aspergillus conidia and hyphae in the presence or absence of ETI CFTR modulator therapy with bulk RNA transcriptomics and RT-PCR used to analyse Type I/III interferon genes. Effects of exogenous type I and III interferons on CF-neutrophil antifungal effector function was further characterised.

Findings: CFTR modulator (ETI) therapy was associated with a significant reduction in Aspergillus biomarkers alongside use of corticosteroid and anti-fungal therapy. In vitro Aspergillus stimulation enriched the Type I/III interferome in CFTR-corrected BECs compared to CF BECs, with ETI therapy partially restoring type I/III interferon gene expression in CF BECs. Administration of exogenous IFNλ1 increased anti-fungal killing in CF neutrophils without increased reactive-oxygen species or neutrophil extracellular trap production.

Interpretation: CFTR modulators have led to improved clinical outcomes in CF related Aspergillus-related lung disease potentially due to partial restoration of the host antifungal epithelial type I/III interferon response. Exogenous IFNλ1 further improved antifungal killing capacity of CF-neutrophils presenting a plausible future therapeutic strategy.

Funding: This study was funded by the Cystic Fibrosis Trust (SRC015).

Background: High-grade serous ovarian carcinoma (HGSOC) presents a significant therapeutic challenge. Late-stage disease is frequently associated with peritoneal carcinomatosis. The peritoneal metastases exhibit a unique tumour microenvironment (TME) distinct from the primary tumours and other metastatic sites. Understanding the critical influence of the extracellular matrix (ECM) in shaping the tumour phenotype is essential for the development of effective new therapies.

Methods: This study introduces a three-dimensional (3D) model of HGSOC peritoneal metastases using a porcine decellularised peritoneal-derived ECM scaffold, referred to as peritoneal matrix (PerMa).

Findings: We show that the decellularisation maintains the structural integrity and composition of ECM molecules. Comparative analysis reveals structural, compositional, and mechanical similarities between porcine and human peritoneal matrices, underscoring the porcine model's translational relevance for modelling human peritoneum physiology. The PerMa supports the 3D growth of HGSOC cell lines. The model enables the assessment of sensitivity to traditional chemotherapy and novel cell-based immunotherapy through confocal imaging and quantification of cell volume.

Interpretation: Our model offers a valuable platform for investigating peritoneal carcinomatosis in HGSOC, with the potential to contribute significantly to developing novel therapeutic approaches.

Funding: Financial support was provided by the University of Bergen, Helse Vest RHF (F-12183-D10616, 779, 911182, 912035, and 912146), Helse Bergen HF (240222), the Norwegian Cancer Society (6833652 and 182735), the Research Council of Norway grants (250317, 326300, 223250, 262652, and 295910), the Novo Nordisk Foundation (NNF21OC0070381), the Kolbjørn Brambani Legat for Kreftforskning, the National Institute of Health (R01CA199646) and the Swedish Cancer Society (21 1888 Pj).

Background: The presence of cystic fibrosis (CF) in diverse groups is known but its incidence is not established in non-European populations. We predict that the number of births with CF in populations with non-European and European ancestry are comparable, and that sampling the general population may inform improved diagnostic and therapeutic strategies.

Methods: We curated pathogenic CFTR variants from the Genome Aggregation Database (gnomAD, versions 2.1 and 4.0) for different groups and estimated the incidence per 100,000 births using Hardy-Weinberg equilibrium. To estimate annual births with CF, we used United Nations population statistics. Additionally, we estimated the percentages of alleles missed by common screening panels and those not approved for treatment using highly effective modulator therapies (HEMT).

Findings: CF affects 44-52, 11-14, 7, 6, 4, and 0.2-1 births per 100,000 in European, African/African American, Admixed American, South Asian, East Asian, and Middle Eastern groups, respectively. Due to higher birth rates, the estimated annual births with CF in India (1426-1582) and Brazil (330-390) are comparable to those in the US (∼1000) and UK (∼300). The expanded Wisconsin screening panel misses the fewest variants in all groups (1-30% pathogenic alleles), while other screening panels miss 25->70% of pathogenic alleles from non-European groups. Of the pathogenic alleles in non-European groups, 25-40% were not approved for treatment using HEMT.

Interpretation: Absolute number of CF births in South America, Asia, and Africa may be comparable to those in the US and Europe. Improved diagnostics, therapeutics, and access to HEMT will benefit thousands of people with CF globally.

Funding: None.