Biology subjects

Dettmer, K.

Publications and source records attributed to Dettmer, K..

4 recordsLinked to original sources

bioRxiv2026

Glutamine and GLS1 are key metabolic checkpoints that Limit T cell Infiltration and Function in HNSCC

Head and neck squamous cell carcinoma (HNSCC) is characterized by poor survival and limited benefit from immune checkpoint blockade (ICB), underscoring the need to define targetable mechanisms of immune escape. In a prospective, patient-centered study, we investigated how tumor metabolic reprogramming impairs T cell function and drives ICB resistance. Targeted metabolomics identified two dominant and distinct tumor states: the Warburg phenotype and glutamine deprivation and revealed increased tumor-specific glutamine to glutamate turnover. Integrating spatial metabolic imaging with immunohistochemistry linked these states to immune-cold and immune-excluded tumor architectures. Metabolic states selectively reduced the expression of T cell chemokine receptors highly abundant and prognostic in HNSCC. Accordingly, T cell migration into tumor spheroids was reduced at lower glutamine concentrations. Interfering with glutamine metabolism by pharmacologic inhibition or genetic deletion of glutaminase-1 markedly increased tumor susceptibility to immune cell-mediated cytotoxicity in vitro and ex vivo and sensitized patient-derived tumor fragments (PDTFs) to ICB. This effect extended beyond glutamine restoration and involved disruption of glutathione-dependent ROS defense, impaired tumor proliferation, and increased MHC expression in tumor cells. Consistently, high expression of genes involved in glutamine and glutathione metabolism associated with reduced ICB response in patients. In contrast to HNSCC, other tumor entities including breast cancer show low glutaminase-1 expression. Accordingly, breast cancer PDTFs were not responsive to glutaminase-1 inhibition. Together, these data identify glutaminase-1 as a metabolic checkpoint driving immune escape in HNSCC, and support guided patient stratification for metabolism-targeted immunotherapy, similar to current precision approaches for mutation targeted drugs.

cancer biology↗

bioRxiv2026

DESI-MS-Based Analysis of Drug Distribution in Human Renal Cystic Tissue Using the Chorioallantoic Membrane (CAM) as a 3D In Vivo Model

The chorioallantoic membrane (CAM) model represents a promising three-dimensional in vivo platform for preclinical drug testing in human tissues. In this study, we investigated whether the tissue penetration and distribution of benzbromarone, a known inhibitor of the Ca2+ activated chloride channel TMEM16A and potential therapeutic agent for autosomal dominant polycystic kidney disease (ADPKD), can be successfully visualized in human renal cyst tissue cultured on the CAM. To this end, desorption electrospray ionization mass spectrometry imaging (DESI-MSI) combined with an ultrahigh-resolution time-of-flight mass spectrometer was employed. We achieved spatially resolved molecular mapping of endogenous metabolites and lipids as well as the applied compound. MSI enabled clear differentiation between CAM and cystic tissue based on their distinct lipid profiles. Benzbromarone was reproducibly detected in the cyst specimens and exhibited selective accumulation along the cyst epithelium, which is considered the principal site of action. These observations were complemented by multivariate analyses including Uniform Manifold Approximation and Projection (UMAP), and sparse multinomial logistic zero-sum classification. The data-driven approach confirmed molecular differences between tissue types and allowed accurate classification of drug-treated and untreated regions. This study demonstrates that topically applied benzbromarone penetrates human renal cyst tissue in the CAM model and localizes to pharmacologically relevant tissue regions, notably the location of the Ca2+ activated chloride channel TMEM16A in the epithelial lining. The integration of high-resolution DESI-MSI with advanced statistical analysis provides a robust and label-free method to study drug distribution in human tissue grafts. Our findings contribute to the advancement of translational research in analytical chemistry and pharmacology.

biochemistry↗

bioRxiv2026

Kidney disease reprograms microbiome-host signaling to promote heart failure

BackgroundHeart failure is prevalent in chronic kidney disease (CKD) and linked to chronic inflammation. CKD-typical gut microbiome dysbiosis may stimulate inflammation, as bacterial aromatic metabolites are highly abundant and engage transcriptional programs through the aryl hydrocarbon receptor (AhR). Whether this axis drives cardiac remodeling and is therapeutically targetable remains unknown. MethodsWe used the subtotal nephrectomy model (STNx) and microbiome depletion by oral antibiotics. We investigated cardiac and renal function, AhR activity, metabolite profiles, and immunophenotypes by flow cytometry and transcriptomics. Candidate metabolite indoxyl sulfate (IxS) was tested in experimental HFpEF. In vivo and in vitro AhR inhibition (AhRi) was performed using a clinically tested compound. Mechanistic studies were performed in primary human and murine cardiac fibroblasts and T cells, as well as translational validation using UK Biobank data. ResultsMicrobiome depletion lowered bacterial metabolites and attenuated cardiac fibrosis and diastolic dysfunction in STNx, identifying AhR-driven expansion of interleukin-17A (IL-17A)-producing T helper cells (TH17) as key effector. Plasma IL-17A was stage-dependently elevated in CKD patients, particularly in HFpEF, and associated with all-cause mortality. Bacterial metabolite IxS promoted TH17 polarization and exacerbated cardiac dysfunction in HFpEF. AhRi using a small molecule inhibitor reduced TH17 abundance and attenuated cardiac fibrosis in STNx. Mechanistically, AhR and IL-17A signaling synergistically induced a conserved pro-fibrotic phenotype in human and murine cardiac fibroblasts, and AhR inhibition blocked ECM production in response to CKD patient serum. ConclusionA microbiome-AhR-IL-17A axis drives CKD-associated cardiac fibrosis. AhRi prevents remodeling, highlighting a potential therapeutic avenue to prevent cardiorenal multimorbidity.

immunology↗

bioRxiv2022

Macrophages inhibit Coxiella burnetii by the ACOD1-itaconate pathway for containment of Q fever

Infection with the intracellular bacterium Coxiella (C.) burnetii can cause chronic Q fever with severe complications and limited treatment options. Here, we identify the enzyme cis- aconitate decarboxylase 1 (ACOD1 or IRG1) and its product itaconate as protective host immune pathway in Q fever. Infection of mice with C. burnetii induced expression of several anti-microbial candidate genes, including Acod1. In macrophages, Acod1 was essential for restricting C. burnetii replication, while other antimicrobial pathways were dispensable. Intratracheal or intraperitoneal infection of Acod1-/- mice caused increased C. burnetii burden, significant weight loss and stronger inflammatory gene expression. Exogenously added itaconate restored pathogen control in Acod1-/- mouse macrophages and blocked replication in human macrophages. In axenic cultures, itaconate directly inhibited growth of C. burnetii. Finally, treatment of infected Acod1-/-mice with itaconate efficiently reduced the tissue pathogen load. Thus, ACOD1-derived itaconate is a key factor in the macrophage-mediated defense against C. burnetii and may be exploited for novel therapeutic approaches in chronic Q fever.

immunology↗