Biology subjects

Radkevich, E.

Publications and source records attributed to Radkevich, E..

4 recordsLinked to original sources

bioRxiv2025

Integrative Omics Identifies Candidate Plasma Biomarkers and Cellular Targets Associated with Thoracic Aortic Aneurysm

ObjectivesTo define the cellular landscape of thoracic aortic aneurysm (TAA) and identify circulating biomarkers associated with disease burden. BackgroundTAA is marked by progressive aortic wall weakening and dilation, predisposing to rupture and dissection. However, its cellular architecture remains incompletely defined, and reliable circulating biomarkers are lacking. MethodsSingle-cell RNA sequencing was performed on 17 aortic tissue samples from 10 patients undergoing TAA repair and integrated with publicly available datasets to characterize disease-associated cell states. In parallel, tomographic imaging and plasma proteomics were used to identify biomarkers associated with aortic diameter. Key findings were further assessed through integration with single-cell data, external validation, and in vitro stimulation of primary human adventitial fibroblasts with fibroblast growth factor 23 (FGF-23). ResultsWe identified 25 cellular subsets, including macrophages, endothelial cells, vascular smooth muscle cells, and fibroblasts, with substantial heterogeneity in cellular composition and transcriptional state. Genome-wide association study candidate genes, including JUN and TPM3, showed cell type-specific upregulation. Plasma proteomics identified multiple biomarkers associated with aortic diameter, of which FGF-23 was independently validated in the UK Biobank as elevated in individuals with TAA. FGFR1, the receptor for FGF-23, was selectively expressed in fibroblasts and subsets of vascular smooth muscle cells, with strongest downstream signaling in fibroblasts. FGF-23 stimulation induced inflammatory and extracellular matrix remodeling programs in primary human adventitial fibroblasts. ConclusionsThese findings define the cellular landscape of TAA and identify the FGF-23-FGFR1 axis as a biomarker-linked pathway that may contribute to aneurysm progression. Condensed AbstractThoracic aortic aneurysm (TAA) is characterized by progressive aortic dilation and risk of rupture, yet its cellular architecture and circulating biomarkers remain incompletely defined. We performed single-cell RNA sequencing on 17 aortic samples from 10 patients and integrated these data with public datasets to define the cellular landscape of TAA. In parallel, imaging and plasma proteomics (n=10) were used to identify biomarkers associated with aortic diameter. We identified 25 cellular subsets, including macrophages, endothelial cells, vascular smooth muscle cells, and fibroblasts, with notable transcriptional heterogeneity and cell type-specific upregulation of GWAS-associated genes (e.g., JUN, TPM3). Plasma proteomics identified fibroblast growth factor 23 (FGF-23) as associated with aortic diameter and elevated in TAA in the UK Biobank. FGFR1, its receptor, was selectively expressed in fibroblasts and VSMCs, and FGF-23 stimulation induced inflammatory and extracellular matrix remodeling programs in fibroblasts. These findings link a circulating biomarker to stromal cell signaling in TAA. HighlightsO_LIIntegrative single-cell RNA sequencing defined a diverse cellular landscape in thoracic aortic aneurysm tissue, identifying 25 distinct cell populations. C_LIO_LICross-dataset harmonization revealed marked differences in cellular composition across studies while supporting shared stromal and immune programs in thoracic aortic aneurysm. C_LIO_LIPlasma proteomics identified FGF-23 as a candidate biomarker associated with aortic diameter and independently linked to thoracic aortic aneurysm presence in the UK Biobank C_LIO_LIFGFR1 was enriched in fibroblasts and subsets of vascular smooth muscle cells, and FGF-23 induced inflammatory and extracellular matrix remodeling programs in human primary adventitial fibroblasts. C_LI

cell biology↗

bioRxiv2024

Dendritic cells type 1 control the formation, maintenance, and function of tertiary lymphoidstructures in cancer

Tertiary lymphoid structures (TLS) are organized immune cell aggregates that arise in chronic inflammatory conditions. In cancer, TLS are associated with better prognosis and enhanced response to immunotherapy, making these structures attractive therapeutic targets. However, the mechanisms regulating TLS formation and maintenance in cancer are incompletely understood. Using spatial transcriptomics and multiplex imaging across various human tumors, we found an enrichment of mature dendritic cells (DC) expressing high levels of CCR7 in TLS, prompting us to investigate the role of DC in the formation and maintenance of TLS in solid tumors. To address this, we developed a novel murine model of non-small cell lung cancer (NSCLC) that forms mature TLS, containing B cell follicles with germinal centers and T cell zones with T follicular helper cells (TFH) and TCF1+PD-1+ progenitor exhausted CD8+ T cells (Tpex). Here we show that, during the early stages of tumor development, TLS formation relies on IFN{gamma}-driven maturation of the conventional DC type 1 (cDC1) subset, their migration to tumor-draining lymph nodes (tdLN), and recruitment of activated T cells to the tumor site. As tumors progress, TLS maintenance becomes independent of T cell egress from tdLN, coinciding with a significant reduction of cDC1 migration to tdLN. Instead, mature cDC1 accumulate within intratumoral CCR7 ligand-enriched stromal hubs. Notably, timed depletion of cDC1 or disruption of their migration to these stromal hubs after TLS are formed alters TLS maintenance. Importantly, we found that cDC1-mediated antigen presentation to both CD4+ and CD8+ T cells and intact CD40 signaling, is critical for the maintenance of TLS, the preservation of the TFH cell pool, the formation of germinal center and the production of tumor-specific IgG antibodies. These findings underscore the key role of mature cDC1 in establishing and maintaining functional TLS within tumor lesions and highlight the potential for cDC1-targeting therapies as a promising strategy to enhance TLS function and improve anti-tumor immunity in patients with cancer.

immunology↗

bioRxiv2024

Informing biologically relevant signal from spatial transcriptomic data

Visium is a spatial sequencing technology that utilizes messenger RNA (mRNA) to spatially map gene expression within tissues. Despite its potential, research utilizing deconvolution tools and exploring microenvironment dynamics remains challenging. We address this gap by benchmarking deconvolution tools across diverse biological contexts, identifying optimal methodologies. Subsequently, we introduce a novel pipeline integrating advanced deconvolution techniques and novel tools for reproducible tissue microenvironment analysis. Through this approach, we uncover intricate immune aggregate biology, highlighting the power of our methodology in unraveling complex biological phenomena.

bioinformatics↗

bioRxiv2024

HLA-E and NKG2A Mediate Resistance to M. bovis BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer

BackgroundBacillus Calmette-Guerin (BCG) is the standard of care treatment for high-risk non-muscle-invasive bladder cancer (NMIBC), yet many patients develop recurrent disease despite evidence of ongoing immune activation. We investigated mechanisms of immune escape in BCG-unresponsive tumors and evaluated the therapeutic potential of targeting the HLA-E/NKG2A axis. MethodsSingle-cell RNA sequencing, spatial immunophenotyping, proteomic profiling, and functional ex vivo assays were performed using tumors and urine samples from patients with BCG-naive and BCG-unresponsive NMIBC. ResultsBCG-unresponsive tumors were enriched for HLA-E-expressing malignant cells compared with BCG-naive tumors. Increased HLA-E expression was associated with enhanced IFN-{gamma} signaling and was induced by IFN-{gamma} stimulation in primary tumor cells and bladder cancer tumor lines. Spatial analyses demonstrated accumulation of NKG2A+ NK and CD8 T cells in proximity to HLA-Ehigh tumor cells, with increased NKG2A:HLA-E interactions in BCG-unresponsive tumors. Despite high expression of cytotoxic mediators, NKG2A+ effector cells displayed impaired degranulation. Blockade of NKG2A with monalizumab restored degranulation of and cytotoxicity by tumor-infiltrating lymphocytes in autologous tumor co-cultures. ConclusionsBCG-unresponsive NMIBC tumors are enriched for HLA-E-expressing tumor cells and NKG2A+ effector lymphocytes, with increased engagement of the HLA-E/NKG2A axis within the tumor microenvironment. These findings identify the HLA-E/NKG2A axis as a therapeutic vulnerability and provide a rationale for clinical evaluation of NKG2A blockade as a bladder-sparing strategy for patients with BCG-unresponsive disease.

cancer biology↗