Lymphoid Follicle Spatial Transcriptomics Resolve an Emphysema-Specific B Cell Signature in COPD
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE237120 | GEO | 2023/11/21
REPOSITORIES: GEO
Similar Datasets
Project description:Lymphotoxin β-receptor-signalling orchestrates lymphoid neogenesis and subsequent tertiary lymphoid structures (TLS) associated with severe chronic inflammatory diseases spanning multiple organ systems. How LTβR-signalling drives chronic tissue damage particularly in the lung, which mechanism(s) regulate this process, and whether LTβR-blockade might be of therapeutic value has remained unclear. Here we demonstrate increased lymphotoxin expression of LTbR-ligands on myeloid and adaptive and innate immune-cells, enhanced non-canonical NF-κB signalling and enrichment of LTβR-target gene expression in epithelial cells of lungs from patients and mice with smoking-associated chronic obstructive pulmonary disease (COPD). Accordingly, Therapeutic inhibition of LTβR-signalling in young and aged mice with COPD disrupted TLS, reverted lung tissue destruction, airway-fibrosis and systemic muscle wasting. Mechanistically, we identified that LTβR-signalling blockade leads to diminished cell-death, concomitantly reactivated endogenous Wnt/β-catenin-signalling in alveolar epithelial cells and reduced TGFβ-signalling in airways. These findings highlight LTβR as a viable therapeutic target against TLS induced tissue damage that translates into novel anti-inflammatory, regenerative strategies to treat COPD.
2020-07-10 | GSE125521 | GEO
Project description:Most high grade serous ovarian cancers (HGSOC) originate in the fallopian tube but spread to the ovary and peritoneal cavity, highlighting the need to understand antitumor immunity across HGSOC sites. Using spatial analyses, we discover that tertiary lymphoid structures (TLS) within ovarian tumors are less developed compared with TLS in fallopian tube or omental tumors. We reveal transcriptional differences across a spectrum of lymphoid structures, demonstrating that immune cell activity increases when residing in more developed TLS and produce a prognostic, spatially derived TLS signature from HGSOC tumors. We interrogate TLS-adjacent stroma and assess how normal mesenchymal stem cells MSCs (nMSCs) may support B cell function and TLS, contrary to cancer-educated MSCs (CA-MSCs) which negate the prognostic benefit of our TLS signature, suggesting that pro-tumorigenic stroma could limit TLS formation.
2024-10-10 | GSE276935 | GEO
Project description:Tertiary lymphoid structures (TLS are lymph node-like immune cell clusters that emerge during chronic inflammation in non-lymphoid organs like the kidney, but their origin remains not well understood. Here we show, using conditional deletion strategies of the canonical Notch signaling mediator Rbpj, that loss of endothelial Notch signaling in adult mice induces the spontaneous formation of bona fide TLS in the kidney, liver and lung, based on molecular, cellular and structural criteria. These TLS form in a stereotypical manner around parenchymal arteries, while secondary lymphoid structures remained largely unchanged. This effect is mediated by endothelium of blood vessels, but not lymphatics, since a lymphatic endothelial-specific targeting strategy did not result in TLS formation, and involves loss of arterial specification and concomitant acquisition of a high endothelial cell phenotype, as shown by transcriptional analysis of kidney endothelial cells. This indicates a so far unrecognized role for vascular endothelial cells and Notch signaling in TLS initiation.
2022-02-24 | GSE193544 | GEO
Project description:The presence of B cells in tumors have been recently reported to predict the better prognosis of patients with cancer. B cells were found primarily in so-called tertiary lymphoid structures (TLSs) in tumor. TLSs are ectopic lymphoid aggregates that form at sites of micro-secondary lymphoid organs, including a B cell follicle with a network of follicular dendritic cells (FDCs) surrounded by T cell zone composed of CD4+ T follicular helper (Tfh) cells and CD8+ T cells and high endothelial venules (HEVs). The presence of TLS is associated with positive outcomes in several human malignancie and More importantly, TLSs enriched in B cells have been proven beneficial for response to ICB in multiple types of cancer. Here, we establish tobacco-associated HNSCC mouse model with TLS enrichment by overexpression of LIGHT in tumor to evaluate the TLS influence in HPV- HNSCC and immunotherapy in HPV- HNSCC.
2022-03-03 | GSE197559 | GEO
Project description:Emerging data indicate that B-cells play a key role in cancer suppression, particularly when aggregated in tertiary lymphoid-like structures (TLS). Here, we used single-cell and bulk RNA sequencing of endometrial cancers (ECs) and found L1-cell adhesion molecule L1CAM to be significantly associated with TLS. Immunohistochemical (IHC) expression of L1CAM was restricted to the germinal centre (GC) of mature TLS, where it co-localised with follicular dendritic cell (FDC) marker CD21. Tumours surrounded by L1CAM-positive TLS were identified across all molecular EC subgroups, but enriched in mismatch repair deficient (MMRd) and polymerase-epsilon mutant (POLEmut) EC, especially when TP53 mutations were also present. Importantly, L1CAM-positive TLS appeared an independent favourable predictor of EC recurrence and death, and significantly improved the current prognostic molecular EC classification based on clinicopathological and molecular factors. Our data suggest a pivotal role of TLS in predicting outcome of EC patients, and establishes L1CAM as a simple and widely available biomarker of TLS in clinical care.
2021-07-15 | GSE180091 | GEO
Project description:The presence of intratumoral tertiary lymphoid structures (TLS) is associated with positive clinical outcomes and responses to immunotherapy in cancer. Here, we used spatial transcriptomics to examine the nature of B cell responses within TLS in renal cell carcinoma (RCC). B cells were enriched in TLS, and therein, we could identify all B cell maturation stages toward plasma cell (PC) formation. B cell repertoire analysis revealed clonal diversification, selection, expansion in TLS, and the presence of fully mature clonotypes at distance. In TLS+ tumors, IgG- and IgA-producing PCs disseminated into the tumor beds along fibroblastic tracks. TLS+ tumors exhibited high frequencies of IgG-producing PCs and IgG-stained and apoptotic malignant cells, suggestive of anti-tumor effector activity. Therapeutic responses and progression-free survival correlated with IgG-stained tumor cells in RCC patients treated with immune checkpoint inhibitors. Thus, intratumoral TLS sustains B cell maturation and antibody production that is associated with response to immunotherapy, potentially via direct anti-tumor effects.
2022-03-03 | GSE175540 | GEO
Project description:T lymphocytes can efficiently counteract the growth of tumors within the tumor microenvironment. Specialized immune-interacting fibroblasts, termed fibroblastic reticular cells (FRC) are responsible for the formation of specialized niches promoting immune cell activation in secondary lymphoid organs and originate from embryonic progenitors. FRCs have also been identified in tertiary lymphoid structures (TLS) in tumor tissues. However, the identity and differentiation of TLS-associated FRC subsets that promote intra-tumoral T cell activity have remained unexplored. Here, we employed single cell RNA-sequencing of fibroblasts and immune cells, sampled from subpleural margin, central margin and unaffected lung tissue in non small cell lung cancer (NSCLC), demonstrating the formation of specific tumor T cell environments (TTEs) underpinned by CCL19-expressing FRCs. We detected tumor-specific FRC subsets namely CCL19-expressing TRCs and perivascular reticular cells (PRCs) interacting with intratumoral T cells, and thus regulating FRC differentiation and T cell activation. Our results highlight a remarkable functionality of FRCs to efficiently determine protective antitumoral T cell responses in NSCLC.
2024-11-19 | E-MTAB-13710 | biostudies-arrayexpress
Project description:Immune aggregates organized as tertiary lymphoid structures (TLS) are observed within kidneys of systemic lupus erythematosus (SLE) patients with lupus nephritis (LN). We characterized renal TLS in lupus-prone (NZBxNZW) F1 mice with respect to cell composition and vessel formation. Ribonucleic acid (RNA) sequencing was performed on transcriptomes isolated from Lymph nodes (LyN), macro-dissected TLS from kidneys, and total kidneys of mice at different disease stages by using Ion Torrent Personal Genome Machine (Ion PGM) and RNAseq from Illumina. Formation of TLS was found in anti-dsDNA antibody positive mice and the structures were organized as interconnected large networks with distinct T and B cell zones with adjacent dendritic cells, macrophages, plasma cells, high endothelial venules, supporting follicular dendritic cells network, and functional germinal centers. Comparison of gene profiles of whole kidney, renal TLS and LyN revealed a similar gene signature of TLS and LyN. The upregulated genes within the kidneys of lupus-prone mice during the development of LN reflected the TLS formation, while the downregulated genes were involved in metabolic processes of the kidney cells. A comparison with human LN gene expression revealed similar upregulated genes as observed during the development of murine LN and TLS. We conclude that kidney TLS have a similar cell composition, structure and gene signature as LyN, and therefore may function as a kidney specific type of LyN.
2020-07-30 | GSE155405 | GEO
Project description:The key role of tertiary lymphoid structures in autoimmune and non-autoimmune conditions has been recently appreciated. While many of the molecular mechanisms involved in tertiary lymphoid structure formation have been identified, their cellular sources and temporal and spatial relationship remain unknown. Using single-cell RNA-sequencing, spatial transcriptomics and proteomics of minor salivary glands of patients with Sjogren’s disease and Sicca Syndrome, ex-vivo and in vivo functional studies, we construct a cellular and spatial map of key components involved in the formation and function of tertiary lymphoid structures. We confirm the presence of a fibroblast cell state and identify an undescribed pericyte/mural cell state with potential immunological functions. The identification of novel cellular properties associated with these structures and the molecular and functional interactions identified by this analysis provide key therapeutic cues for tertiary lymphoid structures associated conditions in autoimmunity and cancer.
2024-07-17 | GSE272410 | GEO
Project description:The key role of tertiary lymphoid structures in autoimmune and non-autoimmune conditions has been recently appreciated. While many of the molecular mechanisms involved in tertiary lymphoid structure formation have been identified, their cellular sources and temporal and spatial relationship remain unknown. Using single-cell RNA-sequencing, spatial transcriptomics and proteomics of minor salivary glands of patients with Sjogren’s disease and Sicca Syndrome, ex-vivo and in vivo functional studies, we construct a cellular and spatial map of key components involved in the formation and function of tertiary lymphoid structures. We confirm the presence of a fibroblast cell state and identify an undescribed pericyte/mural cell state with potential immunological functions. The identification of novel cellular properties associated with these structures and the molecular and functional interactions identified by this analysis provide key therapeutic cues for tertiary lymphoid structures associated conditions in autoimmunity and cancer.
2024-07-17 | GSE272409 | GEO