Transgelin 2 guards T cell lipid metabolism and antitumour function.

Mounting effective immunity against pathogens and tumours relies on the successful metabolic programming of T cells by extracellular fatty acids. Fatty-acid-binding protein 5 (FABP5) has a key role in this process by coordinating the efficient import and trafficking of lipids that fuel mitochondrial respiration to sustain the bioenergetic requirements of protective CD8 T cells. However, the mechanisms that govern this immunometabolic axis remain unexplored.

High-grade serous ovarian cancer development and anti-PD-1 resistance is driven by IRE1α activity in neutrophils.

High-grade serious ovarian cancer (HGSOC) is an aggressive malignancy that remains refractory to current immunotherapies. While advanced stage disease has been extensively studied, the cellular and molecular mechanisms that promote early immune escape in HGSOC remain largely unexplored. Here, we report that primary HGSO tumors program neutrophils to inhibit T cell anti-tumor function by activating the endoplasmic reticulum (ER) stress sensor IRE1α.

High-grade serous ovarian cancer development and anti-PD-1 resistance is driven by IRE1α activity in neutrophils.

High-grade serous ovarian cancer (HGSOC) is an aggressive malignancy that remains refractory to current immunotherapies. While advanced stage disease has been extensively studied, the cellular and molecular mechanisms that promote early immune escape in HGSOC remain largely unexplored. Here we report that primary HGSO tumors program neutrophils to inhibit T cell anti-tumor function by activating the endoplasmic reticulum (ER) stress sensor IRE1α.

Iron Chelation Therapy Elicits Innate Immune Control of Metastatic Ovarian Cancer.

Iron accumulation in tumors contributes to disease progression and chemoresistance. Although targeting this process can influence various hallmarks of cancer, the immunomodulatory effects of iron chelation in the tumor microenvironment are unknown. Here, we report that treatment with deferiprone, an FDA-approved iron chelator, unleashes innate immune responses that restrain ovarian cancer.

Reduction in transfer of micro-organisms between patients and staff using short-sleeved gowns and hand/arm hygiene in intensive care during the COVID-19 pandemic: A simulation-based randomised trial.

Background: Current personal protective equipment (PPE) practices in UK intensive care units involve "sessional" use of long-sleeved gowns, risking nosocomial infection transmitted via gown sleeves. Data from the first wave of the COVID19 pandemic demonstrated that these changes in infection prevention and control protocols were associated with an increase in healthcare associated bloodstream infections. We therefore explored the use of a protocol using short-sleeved gowns with hand and arm hygiene to reduce this risk.

Inflammatory ER stress responses dictate the immunopathogenic progression of systemic candidiasis.

Recognition of pathogen-associated molecular patterns can trigger the inositol-requiring enzyme 1 α (IRE1α) arm of the endoplasmic reticulum (ER) stress response in innate immune cells. This process maintains ER homeostasis and also coordinates diverse immunomodulatory programs during bacterial and viral infections. However, the role of innate IRE1α signaling in response to fungal pathogens remains elusive.

hMRP8-ATTAC Mice: A New Model for Conditional and Reversible Neutrophil Ablation.

Neutrophils are not only crucial immune cells for the neutralization of pathogens during infections, but they are also key players in tissue repair and cancer. Several methods are available to investigate the in vivo role of neutrophils in these conditions, including the depletion of neutrophils with neutralizing antibodies against Ly6G, or the blockade of neutrophil recruitment with CXCR2 inhibitors. A limited number of transgenic mouse models were generated that rely on the disruption of genes important for neutrophil development or on the injection of diphtheria toxin to induce neutrophil ablation.

Decoding endoplasmic reticulum stress signals in cancer cells and antitumor immunity.

The tumor microenvironment (TME) provokes endoplasmic reticulum (ER) stress in malignant cells and infiltrating immune populations. Sensing and responding to ER stress is coordinated by the unfolded protein response (UPR), an integrated signaling pathway governed by three ER stress sensors: activating transcription factor (ATF6), inositol-requiring enzyme 1α (IRE1α), and protein kinase R (PKR)-like ER kinase (PERK). Persistent UPR activation modulates malignant progression, tumor growth, metastasis, and protective antitumor immunity.

Tumor-Derived Lysophosphatidic Acid Blunts Protective Type I Interferon Responses in Ovarian Cancer.

Unlabelled: Lysophosphatidic acid (LPA) is a bioactive lipid enriched in the tumor microenvironment of immunosuppressive malignancies such as ovarian cancer. Although LPA enhances the tumorigenic attributes of cancer cells, the immunomodulatory activity of this phospholipid messenger remains largely unexplored. Here, we report that LPA operates as a negative regulator of type I interferon (IFN) responses in ovarian cancer.

Tumor-associated macrophages promote intratumoral conversion of conventional CD4 T cells into regulatory T cells via PD-1 signalling.

While regulatory T cells (T) and macrophages have been recognized as key orchestrators of cancer-associated immunosuppression, their cellular crosstalk within tumors has been poorly characterized. Here, using spontaneous models for breast cancer, we demonstrate that tumor-associated macrophages (TAMs) contribute to the intratumoral accumulation of T by promoting the conversion of conventional CD4 T cells (T) into T. Mechanistically, two processes were identified that independently contribute to this process.

The Impact of Pitch and Timbre Cues on Auditory Grouping and Stream Segregation.

In multi-talker listening environments, the culmination of different voice streams may lead to the distortion of each source's individual message, causing deficits in comprehension. Voice characteristics, such as pitch and timbre, are major dimensions of auditory perception and play a vital role in grouping and segregating incoming sounds based on their acoustic properties. The current study investigated how pitch and timbre cues (determined by fundamental frequency, notated as F0, and spectral slope, respectively) can affect perceptual integration and segregation of complex-tone sequences within an auditory streaming paradigm.

Senescence induction dictates response to chemo- and immunotherapy in preclinical models of ovarian cancer.

High-grade serous ovarian carcinoma (HGSOC) is a cancer with dismal prognosis due to the limited effectiveness of existing chemo- and immunotherapies. To elucidate mechanisms mediating sensitivity or resistance to these therapies, we developed a fast and flexible autochthonous mouse model based on somatic introduction of HGSOC-associated genetic alterations into the ovary of immunocompetent mice using tissue electroporation. Tumors arising in these mice recapitulate the metastatic patterns and histological, molecular, and treatment response features of the human disease.

Optineurin Guards IFNγ Signaling in Cancer Cells.

In this issue, Du and colleagues uncover that optineurin functions as a key regulator of IFNγ receptor (IFNGR1) stability in malignant cells. Loss of optineurin in colorectal cancer cells causes IFNGR1 degradation, leading to impaired IFNγ signaling, decreased MHC-I expression, and enhanced ability to evade adaptive immune control..

From High-Throughput Screening to Target Validation: Benzo[]isothiazoles as Potent and Selective Agonists of Human Transient Receptor Potential Cation Channel Subfamily M Member 5 Possessing In Vivo Gastrointestinal Prokinetic Activity in Rodents.

Transient receptor potential cation channel subfamily M member 5 (TRPM5) is a nonselective monovalent cation channel activated by intracellular Ca increase. Within the gastrointestinal system, TRPM5 is expressed in the stoma, small intestine, and colon. In the search for a selective agonist of TRPM5 possessing in vivo gastrointestinal prokinetic activity, a high-throughput screening was performed and compound was identified as a promising hit.

Nanopore metagenomic sequencing to investigate nosocomial transmission of human metapneumovirus from a unique genetic group among haematology patients in the United Kingdom.

Background: Human metapneumovirus (HMPV) infection causes a spectrum of respiratory tract disease, and may be a significant pathogen in the context of immunocompromise. Here, we report direct-from-sample metagenomic sequencing of HMPV using Oxford Nanopore Technology.

Methods: We applied this sequencing approach to 25 respiratory samples that had been submitted to a clinical diagnostic laboratory in a UK teaching hospital.

Transcriptional Signature Derived from Murine Tumor-Associated Macrophages Correlates with Poor Outcome in Breast Cancer Patients.

Tumor-associated macrophages (TAMs) are frequently the most abundant immune cells in cancers and are associated with poor survival. Here, we generated TAM molecular signatures from K14cre;Cdh1;Trp53 (KEP) and MMTV-NeuT (NeuT) transgenic mice that resemble human invasive lobular carcinoma (ILC) and HER2 tumors, respectively. Determination of TAM-specific signatures requires comparison with healthy mammary tissue macrophages to avoid overestimation of gene expression differences.

Mammary tumor-derived CCL2 enhances pro-metastatic systemic inflammation through upregulation of IL1β in tumor-associated macrophages.

Patients with primary solid malignancies frequently exhibit signs of systemic inflammation. Notably, elevated levels of neutrophils and their associated soluble mediators are regularly observed in cancer patients, and correlate with reduced survival and increased metastasis formation. Recently, we demonstrated a mechanistic link between mammary tumor-induced IL17-producing γδ T cells, systemic expansion of immunosuppressive neutrophils and metastasis formation in a genetically engineered mouse model for invasive breast cancer.

Purification of Immune Cell Populations from Freshly Isolated Murine Tumors and Organs by Consecutive Magnetic Cell Sorting and Multi-parameter Flow Cytometry-Based Sorting.

It is well established that tumors evolve together with nonmalignant cells, such as fibroblasts, endothelial cells, and immune cells. These cells constantly entangle and interact with each other creating the tumor microenvironment. Immune cells can exert both tumor-promoting and tumor-protective functions.

Exploiting the Immunomodulatory Properties of Chemotherapeutic Drugs to Improve the Success of Cancer Immunotherapy.

Cancer immunotherapy is gaining momentum in the clinic. The current challenge is to understand why a proportion of cancer patients do not respond to cancer immunotherapy, and how this can be translated into the rational design of combinatorial cancer immunotherapy strategies aimed at maximizing success of immunotherapy. Here, we discuss how tumors orchestrate an immunosuppressive microenvironment, which contributes to their escape from immune attack.

Therapeutic benefit of lentiviral-mediated neonatal intracerebral gene therapy in a mouse model of globoid cell leukodystrophy.

Globoid cell leukodystrophy (GLD) is an inherited lysosomal storage disease caused by β-galactocerebrosidase (GALC) deficiency. Gene therapy (GT) should provide rapid, extensive and lifetime GALC supply in central nervous system (CNS) tissues to prevent or halt irreversible neurologic progression. Here we used a lentiviral vector (LV) to transfer a functional GALC gene in the brain of Twitcher mice, a severe GLD model.

Stable expression and functional characterization of a human nicotinic acetylcholine receptor with α6β2 properties: discovery of selective antagonists.

Background And Purpose: Despite growing evidence that inhibition of α6β2-containing (α6β2*) nicotinic acetylcholine receptors (nAChRs) may be beneficial for the therapy of tobacco addiction, the lack of good sources of α6β2*-nAChRs has delayed the discovery of α6β2-selective antagonists. Our aim was to generate a cell line stably expressing functional nAChRs with α6β2 properties, to enable pharmacological characterization and the identification of novel α6β2-selective antagonists.

Experimental Approach: Different combinations of the α6, β2, β3, chimeric α6/3 and mutant β3(V273S) subunits were transfected in human embryonic kidney cells and tested for activity in a fluorescent imaging plate reader assay.

Identification of novel alpha7 nAChR positive allosteric modulators with the use of pharmacophore in silico screening methods.

The pharmacophore model of in house potent and selective alpha7 nAChR positive allosteric modulators is reported. The model was used to fish out commercially-available compounds from corporate 3D databases. As a result, novel alpha7 positive modulator chemotypes were identified.