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IL-19 as a promising theranostic target to reprogram the glioblastoma immunosuppressive microenvironment.
BACKGROUND: Glioblastoma multiforme (GBM) is an aggressive brain tumor with chemoresistant, immunosuppressive, and invasive properties. Despite standard therapies, including surgery, radiotherapy, and temozolomide (TMZ) chemotherapy, tumors inevitably recur in the peritumoral region. Targeting GBM-mediated immunosuppressive and invasive properties is a promising strategy to improve clinical outcomes. METHODS: We utilized clinical and genomic data from the Taiwan GBM cohort and The Cancer Genome Atlas (TCGA) to analyze RNA sequencing data from patient tumor samples, determining the association of interleukin-19 (Il-19) expression with survival and immunosuppressive activity. Gene set enrichment analysis (GSEA) was performed to assess the relationship between the enrichment levels of immune subsets and Il-19 expression level, and Ingenuity Pathway Analysis (IPA) was used to predict immune responses. Cytokine array and single-cell RNA sequencing were used to examine the effects of IL-19 blockade on tumor immune microenvironment, including tumor-infiltrating leukocyte profiles, differentiation and immunosuppressive genes expression in tumor associated macrophages (TAM). CRISPR Il-19-/- cell lines and Il-19-/- mice were used to examine the role of IL-19 in tumor invasion and M2-like macrophage-mediated immunosuppression. Additionally, we developed novel cholesterol-polyethylene glycol-superparamagnetic iron oxide-IL-19 antibody nanoparticles (CHOL-PEG-SPIO-IL-19), characterized them using dynamic light scattering and transmission electron microscopy, Fourier-Transform Infrared spectroscopy, prussian blue assay, and conducted in vivo magnetic resonance imaging (MRI) in a human glioblastoma stem cell-derived GBM animal model. RESULT: Genomic screening and IPA analysis identified IL-19 as a predicted immunosuppressive cytokine in the peritumoral region, associated with poor survival in patients with GBM. Blocking IL-19 significantly inhibited tumor progression of both TMZ-sensitive (TMZ-S) and TMZ-resistant (TMZ-R) GBM-bearing mice, and modulated the immune response within the GBM microenvironment. Single-cell transcriptome analysis reveal that IL-19 antibody treatment led to a marked increase in dendritic cells and monocyte/macrophage subsets associated with interferon-gamma signaling pathways. IL-19 blockade promoted T cell activation and reprogrammed tumor-associated macrophages toward weakened pro-tumoral phenotypes with reduced Arginase 1 expression. Il19-/- M2-like bone marrow-derived macrophages with lower Arginase 1 level lost their ability to suppress CD8 T cell activation. These findings indicated that IL-19 suppression limits TAM-mediated immune suppression. Molecular studies revealed that IL-19 promotes TMZ-resistant GBM cell migration and invasion through a novel IL-19/WISP1 signaling pathway. For clinical translation, we developed a novel CHOL-PEG-SPIO-IL-19 nanoparticles to target IL-19 expression in glioblastoma tissue. MRI imaging demonstrated enhanced targeting efficiency in brain tumors, with in vivo studies showing prominent hypointense areas in T2*-weighted MRI scans of tumor-bearing mice injected with CHOL-PEG-SPIO-IL-19, highlighting nanoparticle presence in IL-19-expressing regions. Prussian blue staining further confirmed the localization of these nanoparticles in tumor tissues, verifying their potential as a diagnostic tool for detecting IL-19 expression in glioblastoma. This system offers a theranostic approach, integrating diagnostic imaging and targeted therapy for IL-19-expressing GBM. CONCLUSION: IL-19 is a promising theranostic target for reversing immunosuppression and restricting the invasive activity of chemoresistant GBM cells.
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Chinese Immune Multi-Omics Atlas.
Human peripheral blood exhibits molecular and cellular heterogeneity across populations, yet the underlying mechanisms remain unclear. We present the Chinese Immune Multi-Omics Atlas (CIMA), characterizing molecular variations linked to sex, age, and genetic variants through multi-omics analysis of more than 10 million circulating immune cells from 428 Chinese adults. CIMA established an enhancer-driven gene regulatory network comprising 237 robust regulons; identified 9600 eGenes and 52,361 caPeaks at cell type resolution; and revealed pleiotropic associations among immune-related disease risk loci, cis-expression quantitative trait loci (QTLs), and chromatin accessibility QTLs. Furthermore, the cell language model CIMA-CLM predicted chromatin accessibility and evaluated the effects of noncoding variants from chromatin sequences and gene expression. CIMA provides a comprehensive reference for immune-related disease research.
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Generation of a Biliary Tract Cancer Cell Line Atlas Identifies Molecular Subtypes and Therapeutic Targets.
UNLABELLED: Biliary tract cancers (BTC) are aggressive malignancies encompassing intrahepatic and extrahepatic cholangiocarcinoma, gallbladder carcinoma, and ampullary carcinoma. Here, we report integrative analysis of 63 BTC cell lines via multi-omics and genome-scale CRISPR screens. We identify widespread EGFR dependency in BTC, alongside dependencies selective to anatomic subtypes. Additionally, we delineate strategies to overcome therapeutic resistance, with combined EGFR inhibition potentiating targeting of KRAS-mutant and FGFR2 fusion-driven models and SHP2 inhibition effective in the latter context. Clustering RNA/protein expression and dependencies data revealed functional relationships transcending single-gene alterations, with biliary, squamous, or dual biliary/hepatocyte lineage signatures stratifying BTC models. These subtypes exhibit distinct dependency profiles-including cell fate transcription factors GRHL2, TP63, and HNF1B, respectively-and demonstrate prognostic significance in patient samples. Potential subtype-specific targetable vulnerabilities include integrinα3 and the detoxification enzyme UXS1. This cell line atlas reveals therapeutic targets in molecularly defined BTCs, unveils disease subtypes, and provides a resource for therapeutic development. SIGNIFICANCE: This integrative analysis of BTC cell lines defines the landscape of vulnerabilities across BTCs, stratifying distinct subtypes, and provides a key resource for studying disease heterogeneity. The findings highlight strategies for targeting BTCs with specific genomic alterations, as well as broader approaches based on shared molecular programs and essential pathways.
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Stellate cell expression of SPARC-related modular calcium-binding protein 2 is associated with human non-alcoholic fatty liver disease severity.
BACKGROUND & AIMS: Histological assessment of liver biopsies is the gold standard for diagnosis of non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease (NAFLD), despite its well-established limitations. Therefore, non-invasive biomarkers that can offer an integrated view of the liver are needed to improve diagnosis and reduce sampling bias. Hepatic stellate cells (HSCs) are central in the development of hepatic fibrosis, a hallmark of NASH. Secreted HSC-specific proteins may, therefore, reflect disease state in the NASH liver and serve as non-invasive diagnostic biomarkers. METHODS: We performed RNA-sequencing on liver biopsies from a histologically characterised cohort of obese patients (n = 30, BMI >35 kg/m2) to identify and evaluate HSC-specific genes encoding secreted proteins. Bioinformatics was used to identify potential biomarkers and their expression at single-cell resolution. We validated our findings using single-molecule fluorescence in situ hybridisation (smFISH) and ELISA to detect mRNA in liver tissue and protein levels in plasma, respectively. RESULTS: Hepatic expression of SPARC-related modular calcium-binding protein 2 (SMOC2) was increased in NASH compared to no-NAFLD (p.adj <0.001). Single-cell RNA-sequencing data indicated that SMOC2 was primarily expressed by HSCs, which was validated using smFISH. Finally, plasma SMOC2 was elevated in NASH compared to no-NAFLD (p <0.001), with a predictive accuracy of AUROC 0.88. CONCLUSIONS: Increased SMOC2 in plasma appears to reflect HSC activation, a key cellular event associated with NASH progression, and may serve as a non-invasive biomarker of NASH. IMPACT AND IMPLICATIONS: Non-alcoholic fatty liver disease (NAFLD) and its progressive form, non-alcoholic steatohepatitis (NASH), are the most common forms of chronic liver diseases. Currently, liver biopsies are the gold standard for diagnosing NAFLD. Blood-based biomarkers to complement liver biopsies for diagnosis of NAFLD are required. We found that activated hepatic stellate cells, a cell type central to NAFLD pathogenesis, upregulate expression of the secreted protein SPARC-related modular calcium-binding protein 2 (SMOC2). SMOC2 was elevated in blood samples from patients with NASH and may hold promise as a blood-based biomarker for the diagnosis of NAFLD.
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Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients.
Our comprehensive analysis of alternative splicing across 32 The Cancer Genome Atlas cancer types from 8,705 patients detects alternative splicing events and tumor variants by reanalyzing RNA and whole-exome sequencing data. Tumors have up to 30% more alternative splicing events than normal samples. Association analysis of somatic variants with alternative splicing events confirmed known trans associations with variants in SF3B1 and U2AF1 and identified additional trans-acting variants (e.g., TADA1, PPP2R1A). Many tumors have thousands of alternative splicing events not detectable in normal samples; on average, we identified ≈930 exon-exon junctions ("neojunctions") in tumors not typically found in GTEx normals. From Clinical Proteomic Tumor Analysis Consortium data available for breast and ovarian tumor samples, we confirmed ≈1.7 neojunction- and ≈0.6 single nucleotide variant-derived peptides per tumor sample that are also predicted major histocompatibility complex-I binders ("putative neoantigens").
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Integrated multimodal cell atlas of Alzheimer's disease.
Alzheimer's disease (AD) is the most common cause of dementia in older adults. Neuropathological and imaging studies have demonstrated a progressive and stereotyped accumulation of protein aggregates, but the underlying molecular and cellular mechanisms driving AD progression and vulnerable cell populations affected by disease remain coarsely understood. The current study harnesses single cell and spatial genomics tools and knowledge from the BRAIN Initiative Cell Census Network to understand the impact of disease progression on middle temporal gyrus cell types. We used image-based quantitative neuropathology to place 84 donors spanning the spectrum of AD pathology along a continuous disease pseudoprogression score and multiomic technologies to profile single nuclei from each donor, mapping their transcriptomes, epigenomes, and spatial coordinates to a common cell type reference with unprecedented resolution. Temporal analysis of cell-type proportions indicated an early reduction of Somatostatin-expressing neuronal subtypes and a late decrease of supragranular intratelencephalic-projecting excitatory and Parvalbumin-expressing neurons, with increases in disease-associated microglial and astrocytic states. We found complex gene expression differences, ranging from global to cell type-specific effects. These effects showed different temporal patterns indicating diverse cellular perturbations as a function of disease progression. A subset of donors showed a particularly severe cellular and molecular phenotype, which correlated with steeper cognitive decline. We have created a freely available public resource to explore these data and to accelerate progress in AD research at SEA-AD.org.
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A population-scale atlas of blood and tissue in lupus nephritis.
Lupus nephritis (LN), a severe manifestation of Systemic Lupus Erythematosus (SLE), is a heterogeneous disease driven by diverse immune and tissue cell types. We obtained 538K single-cell and 140K single-nuclear profiles from kidney biopsies of 155 LN patients and 30 pre-implantation transplant biopsy controls, along with 325K single-cell blood profiles overlapping many of these patients. We identified key tissue cell types and cell states, and immune cell states; we were able to determine cell states that were tissue specific, and those that were present in the blood. We observed that LN pathological features are significantly associated with cell states using differential gene expression and Covarying Neighborhood Analysis (CNA). These analyses revealed broad changes in cell states associated with irreversible chronic tissue damage. After controlling for the effects of ongoing tissue damage, we observed that expansion of key glomerular and Scar Associated Macrophages (SAMs) populations tracked with increasing inflammatory disease activity. SAMs appear to drive LN fibrosis and, in active disease, infiltrate the glomeruli more than other myeloid cells. These observations strongly support that therapeutic targeting of myeloid populations may offer an as-of-yet unproven strategy to prevent renal inflammation and ongoing kidney damage in LN.
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Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics.
Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.
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Deciphering state-dependent immune features from multi-layer omics data at single-cell resolution.
Current molecular quantitative trait locus catalogs are mostly at bulk resolution and centered on Europeans. Here, we constructed an immune cell atlas with single-cell transcriptomics of >1.5 million peripheral blood mononuclear cells, host genetics, plasma proteomics and gut metagenomics from 235 Japanese persons, including patients with coronavirus disease 2019 (COVID-19) and healthy individuals. We mapped germline genetic effects on gene expression within immune cell types and across cell states. We elucidated cell type- and context-specific human leukocyte antigen (HLA) and genome-wide associations with T and B cell receptor repertoires. Colocalization using dynamic genetic regulation provided better understanding of genome-wide association signals. Differential gene and protein expression analyses depicted cell type- and context-specific effects of polygenic risks. Various somatic mutations including mosaic chromosomal alterations, loss of Y chromosome and mitochondrial DNA (mtDNA) heteroplasmy were projected into single-cell resolution. We identified immune features specific to somatically mutated cells. Overall, immune cells are dynamically regulated in a cell state-dependent manner characterized with multiomic profiles.
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[Impact of bone metastasis on the prognosis of lung adenocarcinoma patients treated with third-generation EGFR-TKI and the underlying mechanisms].
Objective: To evaluate the impact of bone metastasis on the prognosis of lung adenocarcinoma patients receiving first-line third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and to explore the potential mechanisms by which bone metastasis contributes to EGFR-TKI resistance. Methods: A retrospective analysis was conducted on the clinical data of 370 EGFR-mutant advanced lung adenocarcinoma patients who received first-line treatment with third-generation EGFR-TKI at the First Affiliated Hospital of Nanjing Medical University from January 2019 to June 2024, with follow-up until June 2024. Progression-free survival (PFS) and overall survival (OS) were compared between patients with and without baseline bone metastasis. Survival curves were generated using the Kaplan-Meier method, and differences between groups were assessed by the log-rank test. Univariate and multivariate Cox proportional hazards regression models were applied to identify factors associated with PFS following third-generation EGFR-TKI treatment. Single-cell RNA sequencing (scRNA-seq) was performed on two primary pulmonary tumors and two bone metastatic lesions to characterize transcriptomic differences in cancer cells and immune cells within the tumor microenvironment. Gene ontology (GO) enrichment analysis was applied to identify bone metastasis-specific signaling pathways. Based on immune regulatory genes upregulated in cancer cells from bone metastatic lesions, an immune-regulatory score was constructed using a LASSO-Cox regression model in a training cohort of EGFR-mutant lung adenocarcinoma patients from The Cancer Genome Atlas (TCGA). Patients in both the training cohort and an independent Asian EGFR-mutant lung adenocarcinoma validation cohort were stratified into high-and low-score groups according to the median immune regulatory score, and OS was compared between groups. Results: Among the 370 lung adenocarcinoma patients receiving first-line third-generation EGFR-TKI treatment, 161 patients had baseline bone metastasis [mean age (60±11) years; 70 males], while 209 patients had no baseline bone metastasis [mean age (61±9) years; 80 males]. No significant differences in baseline clinicopathological characteristics were observed between patients with and without bone metastasis (all P>0.05). The median PFS in the bone metastasis group was 27.5 months (95%CI: 22.0-33.1), which was significantly shorter than that in the non-bone metastasis group [59.0 months (95%CI: 32.8-85.1), P<0.001]. The median OS was 46.2 months (95%CI: 40.4-51.9) in the bone metastasis group, whereas the median OS had not yet been reached in the non-bone metastasis group, with a statistically significant difference (P=0.013). Multivariate Cox regression analysis identified bone metastasis as an independent risk factor for PFS (HR=1.74, 95%CI:1.27-2.37, P<0.001). Cancer cells in bone metastatic lesions exhibited upregulation of C-X-C motif chemokine ligand 17 (CXCL17), complement decay-accelerating factor (CD55), interferon regulatory factor 1 (IRF1), E3 ubiquitin-protein ligase pellino homolog 1 (PELI1), solute carrier family 7 member 5 (SLC7A5) and prostaglandin-endoperoxide synthase 2 (PTGS2), which were predominantly enriched in pathways related to immune cell differentiation, chemotaxis, and inflammatory responses. At the immune cell level, lymphoid cells in bone metastatic lesions showed activation of stress response and apoptotic pathways, whereas myeloid cells demonstrated significant activation of cytokine/chemokine signaling and inflammation-related pathways. An immune-regulatory score based on CXCL17, CD55, IRF1, PELI1, SLC7A5, and PTGS2 was constructed. In the TCGA training cohort, the median OS of 41 patients with a high immune-regulatory score was 23.1 months (95%CI: 17.5-28.7), which was significantly shorter than that of patients with a low score [58.5 months (95%CI: 43.0-73.9), P<0.001]. In the independent Asian cohort of 93 EGFR-mutant lung adenocarcinoma patients, the median OS of 46 patients with a high immune-regulatory score was 85.3 months (95%CI: 80.0-not reached), while the median OS in the low-score group was not reached, with a statistically significant difference (P=0.014). Conclusions: Bone metastasis is an adverse prognostic factor for progression-free survival in lung adenocarcinoma patients treated with third-generation EGFR-TKI. Bone metastasis lesions exhibit a distinct immunosuppressive tumor microenvironment in EGFR-mutant advanced lung adenocarcinoma, in which upregulation of immune regulatory genes in cancer cells and dysfunction of immune cells may constitute a potential mechanism underlying resistance to third-generation EGFR-TKI.