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A Unified Metric of Human Immune Health?

IFNγ Production by Functionally Reprogrammed Tregs Promotes Antitumor Efficacy of OX40/CD137 Bispecific Agonist Therapy.

UNLABELLED: Regulatory T cells (Treg) are highly enriched within many tumors and suppress immune responses to cancer. There is intense interest in reprogramming Tregs to contribute to antitumor immunity. OX40 and CD137 are expressed highly on Tregs, activated and memory T cells, and NK cells. In this study, using a novel bispecific antibody targeting mouse OX40 and CD137 (FS120m), we show that OX40/CD137 bispecific agonism induces potent antitumor immunity partially dependent upon IFNγ production by functionally reprogrammed Tregs. Treatment of tumor-bearing animals with OX40/CD137 bispecific agonists reprograms Tregs into both fragile Foxp3+ IFNγ+ Tregs with decreased suppressive function and lineage-instable Foxp3- IFNγ+ ex-Tregs. Treg fragility is partially driven by IFNγ signaling, whereas Treg instability is associated with reduced IL2 responsiveness upon treatment with OX40/CD137 bispecific agonists. Importantly, conditional deletion of Ifng in Foxp3+ Tregs and their progeny partially reverses the antitumor efficacy of OX40/CD137 bispecific agonist therapy, revealing that reprogramming of Tregs into IFNγ-producing cells contributes to the anti-tumor efficacy of OX40/CD137 bispecific agonists. These findings provide insights into mechanisms by which bispecific agonist therapies targeting costimulatory receptors highly expressed by Tregs potentiate antitumor immunity in mouse models. SIGNIFICANCE: The bispecific antibody FS120, an immunotherapy currently being tested in the clinic, partially functions by inducing anti-tumor activity of Tregs, which results in tumor rejection.

GS-TCGA: Gene Set-Based Analysis of The Cancer Genome Atlas.

Most tools for analyzing large gene expression datasets, including The Cancer Genome Atlas (TCGA), have focused on analyzing the expression of individual genes or inference of the abundance of specific cell types from whole transcriptome information. While these methods provide useful insights, they can overlook crucial process-based information that may enhance our understanding of cancer biology. In this study, we describe three novel tools incorporated into an online resource; gene set-based analysis of The Cancer Genome Atlas (GS-TCGA). GS-TCGA is designed to enable user-friendly exploration of TCGA data using gene set-based analysis, leveraging gene sets from the Molecular Signatures Database. GS-TCGA includes three unique tools: GS-Surv determines the association between the expression of gene sets and survival in human cancers. Co-correlative gene set enrichment analysis (CC-GSEA) utilizes interpatient heterogeneity in cancer gene expression to infer functions of specific genes based on GSEA of coregulated genes in TCGA. GS-Corr utilizes interpatient heterogeneity in cancer gene expression profiles to identify genes coregulated with the expression of specific gene sets in TCGA. Users are also able to upload custom gene sets for analysis with each tool. These tools empower researchers to perform survival analysis linked to gene set expression, explore the functional implications of gene coexpression, and identify potential gene regulatory mechanisms.

Identifying employee, workplace and population characteristics associated with COVID-19 outbreaks in the workplace: a population-based study

ObjectivesTo identify risk factors that contribute to outbreaks of COVID-19 in the workplace and quantify their effect on outbreak risk.MethodsWe identified outbreaks of COVID-19 cases in the workplace and investigated the characteristics of the individuals, the workplaces, the areas they work and the mode of commute to work, through data linkages based on Middle Layer Super Output Areas in England between 20 June 2021 and 20 February 2022. We estimated population-level associations between potential risk factors and workplace outbreaks, adjusting for plausible confounders identified using a directed acyclic graph.ResultsFor most industries, increased physical proximity in the workplace was associated with increased risk of COVID-19 outbreaks, while increased vaccination was associated with reduced risk. Employee demographic risk factors varied across industry, but for the majority of industries, a higher proportion of black/African/Caribbean ethnicities and living in deprived areas, was associated with increased outbreak risk. A higher proportion of employees in the 60–64 age group was associated with reduced outbreak risk. There were significant associations between gender, work commute modes and staff contract type with outbreak risk, but these were highly variable across industries.ConclusionsThis study has used novel national data linkages to identify potential risk factors of workplace COVID-19 outbreaks, including possible protective effects of vaccination and increased physical distance at work. The same methodological approach can be applied to wider occupational and environmental health research.

Understanding the leading indicators of hospital admissions from COVID-19 across successive waves in the UK

Abstract Following the end of universal testing in the UK, hospital admissions are a key measure of COVID-19 pandemic pressure. Understanding leading indicators of admissions at the National Health Service (NHS) Trust, regional and national geographies help health services plan for ongoing pressures. We explored the spatio-temporal relationships of leading indicators of hospitalisations across SARS-CoV-2 waves in England. This analysis includes an evaluation of internet search volumes from Google Trends, NHS triage calls and online queries, the NHS COVID-19 app, lateral flow devices (LFDs), and the ZOE app. Data sources were analysed for their feasibility as leading indicators using Granger causality, cross-correlation, and dynamic time warping at fine spatial scales. Google Trends and NHS triages consistently temporally led admissions in most locations, with lead times ranging from 5 to 20 days, whereas an inconsistent relationship was found for the ZOE app, NHS COVID-19 app, and LFD testing, which diminished with spatial resolution, showing cross-correlation of leads between –7 and 7 days. The results indicate that novel surveillance sources can be used effectively to understand the expected healthcare burden within hospital administrative areas though the temporal and spatial heterogeneity of these relationships is a key determinant of their operational public health utility.

Retrospective analysis of Schlafen11 (SLFN11) to predict the outcomes to therapies affecting the DNA damage response

Schlafen 11 (SLFN11) is a gene encoding for a protein involved in the irreversible arrest of cell replication under DNA-damaging stress. SLFN11 is expressed differently across various cancers. When overexpressed, SLFN11 inhibits tumor replication and growth by early recruitment to stressed replication forks, making tumors more sensitive to a range of anti-cancer treatments, including topoisomerase I–II inhibitors, DNA alkylating agents, platinum salts, anti-metabolites, anti-tumor antibiotics, poly ADP-ribose polymerase (PARP) inhibitors and immunotherapies. SLFN11 expression can be silenced in cancer cells through different epigenetic mechanisms, resulting in SLFN11 downregulation and resistance to anti-cancer treatments. In this context, SLFN11 is increasingly being recognized as a promising biomarker for predicting cancer treatment responses. Its expression levels can inform clinical decisions, helping to identify patients most likely to benefit from therapies that exploit replication stress and to select new drug combinations that specifically aim to overcome SLFN11 deficiency.

SLFN11 informs on standard of care and novel treatments in a wide range of cancer models.

BACKGROUND: Schlafen 11 (SLFN11) has been linked with response to DNA-damaging agents (DDA) and PARP inhibitors. An in-depth understanding of several aspects of its role as a biomarker in cancer is missing, as is a comprehensive analysis of the clinical significance of SLFN11 as a predictive biomarker to DDA and/or DNA damage-response inhibitor (DDRi) therapies. METHODS: We used a multidisciplinary effort combining specific immunohistochemistry, pharmacology tests, anticancer combination therapies and mechanistic studies to assess SLFN11 as a potential biomarker for stratification of patients treated with several DDA and/or DDRi in the preclinical and clinical setting. RESULTS: SLFN11 protein associated with both preclinical and patient treatment response to DDA, but not to non-DDA or DDRi therapies, such as WEE1 inhibitor or olaparib in breast cancer. SLFN11-low/absent cancers were identified across different tumour types tested. Combinations of DDA with DDRi targeting the replication-stress response (ATR, CHK1 and WEE1) could re-sensitise SLFN11-absent/low cancer models to the DDA treatment and were effective in upper gastrointestinal and genitourinary malignancies. CONCLUSION: SLFN11 informs on the standard of care chemotherapy based on DDA and the effect of selected combinations with ATR, WEE1 or CHK1 inhibitor in a wide range of cancer types and models.

The effect of Council decision making on the ability of Cambridgeshire communities to develop initiatives that lessen the need for formal health and social care services

Meeting Abstracts of the BACR conference: response and resistance in cancer therapy Abstracts

Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms.

Dysfunctional mitochondria are a hallmark of T cell ageing and contribute to organismal ageing. This arises from the accumulation of reactive oxygen species (ROS), impaired mitochondrial dynamics, and inefficient removal of dysfunctional mitochondria. Both cell-intrinsic and cell-extrinsic mechanisms for removing mitochondria and their byproducts have been identified in T cells. In this review, we explore how T cells manage mitochondrial damage through changes in mitochondrial metabolism, mitophagy, asymmetric mitochondrial inheritance, and mitochondrial transfer, highlighting the impact of these mechanisms on T cell ageing and overall organismal ageing. We also discuss current therapeutic strategies aimed at removing dysfunctional mitochondria and their byproducts and propose potential new therapeutic targets that may reverse immune ageing or organismal ageing.

Rapamycin exerts its geroprotective effects in the ageing human immune system by enhancing resilience against DNA damage

Phenotypic Chemical Screening in CD4+ T Cells to Identify Epigenetic Inhibitors.

Chemical biology provides an attractive approach to identify genes involved in a particular biological process. This screening approach has its advantages because the assays are usually non-destructive, and analysis can be performed even if the mechanism of action is unknown. During an immune reaction, cells upregulate the expression and secretion of small proteins called cytokines that have specific effects on the interactions and communication between cells. Here, we describe the principles and steps involved in the execution of chemical screening for identifying epigenetic inhibitors that affect cytokine production in differentiated Th1, Th2, and Th17 cells. Our approach provides a rationale for identifying epigenetic chemical compounds that are capable of controlling CD4+ T-cell cytokine function that may be beneficial for treating inflammatory diseases.

Synovial tissue atlas in juvenile idiopathic arthritis reveals pathogenic niches associated with disease severity.

Precision application of targeted therapies is urgently needed to improve long-term clinical outcomes for children affected by inflammatory arthritis, known as juvenile idiopathic arthritis (JIA). Progress has been hampered by our limited understanding of the cellular basis of inflammation in the target tissue of the disease, the synovial membrane. Here, we analyzed biopsies from the inflamed joints of treatment-naïve children with JIA, early in the course of their disease, using single-cell RNA sequencing, multiplexed immunofluorescence, and spatial transcriptomics to establish a cellular atlas of the JIA synovium. We identified distinct spatial tissue niches, composed of specific stromal and immune cell populations. In addition, we localized genes linked to arthritis severity and disease risk to effector cell populations, including tissue resident SPP1+ macrophages and fibrin-associated myeloid cells. Combined analyses of synovial fluid and peripheral blood from matched individuals revealed differences in cellular composition, signaling pathways, and transcriptional programs across these distinct anatomical compartments. Furthermore, our analysis revealed several pathogenic cell populations that are shared with adult-onset inflammatory arthritis, as well as age-associated differences in tissue vascularity, prominence of innate immunity, and enrichment of TGF-β-responsive stromal subsets that up-regulate expression of disease risk-associated genes. Overall, our findings demonstrate the need for age-specific analyses of synovial tissue pathology to guide targeted treatment strategies in JIA.

Effects of Acute Time-Restricted Eating on Inflammation in Individuals With Psoriasis: Protocol for a Case-Control, Prospective Study.

BACKGROUND: Psoriasis is a chronic inflammatory disease associated with multiple comorbidities, including metabolic syndrome and cardiovascular disease. Although specific dietary interventions, such as intermittent fasting and caloric restriction, have been shown to ameliorate inflammation and promote weight loss, the effect of these interventions independent of weight loss remains unclear. Time-restricted eating (TRE), a type of intermittent fasting, limits the daily eating window to a fixed number of hours. Recent studies suggest TRE may improve immune function in individuals with metabolic syndrome and cardiovascular risk factors. A crucial advantage of TRE over other investigated dietary restriction strategies is its reported high adherence rate, making it a more feasible intervention for long-term use. Therefore, exploring the effects of TRE on metabolic and immunological parameters in psoriasis is warranted. OBJECTIVE: This study was designed to evaluate the effects of short-term, isocaloric TRE, independent of weight loss, on immune cell function and serum metabolite profiles of volunteers with mild-to-moderate psoriasis compared to healthy individuals. METHODS: This case-control, prospective study was performed on 10 healthy male participants and 10 age-, BMI-, and sex-matched individuals with mild-to-moderate psoriasis. All individuals with psoriasis had stable disease and were being treated with topical therapies without any exposure to immunomodulatory biologics. This study was conducted at the National Institutes of Health Clinical Center. Immune profiles, glucose handling, energy expenditure, and participants' weights were assessed at baseline and after 3 days of TRE following a daily 6-hour eating window and 18-hour fast. RESULTS: The trial commenced in June 2021 and was completed in February 2023. A total of 20 participants were enrolled-10 with mild-to-moderate psoriasis and 10 age-, BMI-, and sex-matched healthy individuals. As of the time of manuscript submission, data processing is ongoing. Multiomic datasets, including gene expression, surface and intracellular protein levels, and metabolite profiles, are being generated from peripheral blood mononuclear cells, CD4+-enriched T-cells, and serum samples. The integrated bioinformatics analyses will be reported once the data analysis is completed. CONCLUSIONS: This clinical protocol was designed to characterize the effects of short term (3-day) TRE on psoriasis, independent of weight loss, by comparing immune cell regulatory responses between healthy individuals and those with psoriasis. More specifically, we aim to map the molecular pathways activated by TRE and assess how they affect immune cell composition, activation, and metabolism. Additionally, components of the metabolic response to isocaloric TRE are being explored. Insights into how dietary interventions impact metabolism and the immune system will enhance our understanding of the pathogenesis of psoriasis and may reveal new therapeutic avenues for managing this inflammatory condition. TRIAL REGISTRATION: ClinicalTrials.gov NCT04728165; https://clinicaltrials.gov/study/NCT04728165.

Successful treatment of refractory chilblain lupus erythematosus with bosentan

TASL is required for age-related B cell formation and autoimmunity

The COVIDTrach prospective cohort study on outcomes in 1982 tracheostomised COVID-19 patients during the first and second UK pandemic waves

COVIDTrach is a UK-wide, prospective cohort study evaluating tracheostomised COVID-19 patient outcomes and operator disease transmission. Early in the pandemic controversy surrounded optimal timing of tracheostomy insertion, however meta-analyses have since addressed this uncertainty. We report on our cohort’s data and outcomes to help inform the management of this disease and compare our findings to the literature. Our inclusion criteria were COVID-19 patients aged ≥ 18 undergoing tracheostomy following invasive ventilation. We recorded relevant characteristics, clinical parameters, intra-operative details and outcome data. Predictors for mortality and time to ventilatory wean were determined. Among 1982 patients, there was a 21% post-tracheostomy mortality and median intubation to tracheostomy time of 15 days (IQR 11–21). The median time to successful ventilatory wean post-tracheostomy was 12 days (IQR 7–20). Advancing age, greater FiO2 and PEEP requirements and inotrope or anticoagulant use were associated with increased mortality (p < 0.05) and time to wean success (p < 0.01). Higher CRP predicted increased mortality (p < 0.05), while NIV use and extended pre-tracheostomy ventilation predicted prolonged wean time (p < 0.01). The death risk for tracheostomy performed ≤ 7 or ≥ 14 days of ventilation was equivocal (OR 1.01, 95% CI [0.37–2.72]) but lower between 8 and 14 days (OR = 0.64, 95% CI [0.47–0.86]) (p = 0.01). Eight operators tested positive within two weeks of performing a tracheostomy. Our mortality rates were similar to cohort studies but lower than early versus late tracheostomy designs. In contrast to the literature, we found reduced mortality when tracheostomy was performed 8–14 days post-intubation, with more favourable wean time and wean and decannulation rates.

Immunotherapy for locally advanced head and neck cancer

Perivascular RELMα-positive synovial macrophages recruit monocytes at the onset of inflammatory arthritis.

Macrophages, monocytes and neutrophils are major types of myeloid cells involved in inflammatory diseases, such as rheumatoid arthritis (RA). Recent scRNA-seq studies identified a remarkable diversity of synovial macrophages but, with the exception of lining macrophages, their geographical location and specific roles remain largely unexplored. Here, we localized the RELMα-positive macrophages, predicted to produce high levels of monocyte-recruiting chemokines, to the synovial interstitium and more specifically, to the vicinity of interstitial blood vessels. Using complementary reporter mouse models, CCL2mCherry to label CCL2-producing cells, and CCR2CRE/mKate2 marking CCR2 expressing monocytes, we demonstrated that RELMα-positive perivascular macrophages secrete CCL2 assisting in the recruitment of monocytes predominantly to the synovial interstitium at the onset of antigen-induced arthritis. The inflamed synovial environment guides the differentiation of the recruited monocytes into tissue-resident macrophages, including but not limited to macrophages expressing VSIG4, a characteristic marker of lining macrophages. Thus, RELMα-positive macrophages orchestrate monocyte recruitment to the synovium during articular inflammation, contributing to a local replenishment of synovial lining macrophages.

From complexity to consensus: A roadmap for neutrophil classification.

Neutrophils, previously considered a homogeneous immune cell population, exhibit substantial heterogeneity. Their diverse phenotypic and functional states are shaped by tissue microenvironments and disease-specific signals. However, the lack of robust fate-mapping methods and standardized classification criteria has led to overlapping and ambiguous descriptions of neutrophil heterogeneity. The growing number of neutrophil subpopulations reported in recent years highlights the need for a standardized framework to report how they might relate to each other. Here, we propose a framework that integrates maturation, tissue localization, and functional adaptations. This standardized system aims to harmonize research efforts, foster clearer cross-disciplinary communication, and accelerate both fundamental discoveries in neutrophil biology and the development of targeted therapies.