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IFNγ-IL-17+ CD8 T cells contribute to immunosuppression and tumor progression in human hepatocellular carcinoma.
IL-17-producing CD8 (Tc17) T cells have been shown to play an important role in infection and chronic inflammation, however their implications in hepatocellular carcinoma (HCC) remain elusive. In this study, we performed cytometry by time-of-flight (CyTOF) and revealed the distinctive immunological phenotypes of two IFNγ+ and IFNγ- Tc17 subsets that were preferentially enriched in human HCC. Single-cell RNA-sequencing analysis further revealed regulatory circuits governing the different phenotypes of these Tc17 subsets. In particular, we discovered that IFNγ- Tc17 subset demonstrated pro-tumoral characteristics and expressed higher levels of CCL20. This corresponded to increased tumor infiltration of T regulatory cells (Treg) validated by immunohistochemistry in another independent HCC cohort, demonstrating the immunosuppressive functions of IFNγ- Tc17 subset. Most importantly, higher intra-tumoral proportions of IFNγ- Tc17 were associated with poorer prognosis in patients with HCC and this was further validated in The Cancer Genome Atlas (TCGA) HCC cohort. Taken together, this compendium of transcriptomic and proteomic data of Tc17 subsets sheds light on the immunosuppressive phenotypes of IFNγ- Tc17 and its implications in HCC progression.
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Assessing of programmed cell death gene signature for predicting ovarian cancer prognosis and treatment response.
BACKGROUND: Programmed cell death (PCD) is an overwhelming factor affecting tumor cell metastasis, but the mechanism of PCD in ovarian cancer (OV) is still uncertain. METHODS: To define the molecular subtypes of OV, we performed unsupervised clustering based on the expression level of prognosis related PCD genes in the Cancer Genome Atlas (TCGA)-OV. COX and least absolute shrinkage and selection operator (LASSO) COX analysis were used to identify the OV prognostic related PCD genes, and the genes identified according to the minimum Akaike information criterion (AIC) were the OV prognostic characteristic genes. According to the regression coefficient in the multivariate COX analysis and gene expression data, the Risk Score of OV prognosis was constructed. Kaplan-Meier analysis was conducted to assess the prognostic status of OV patients, and receiver operating characteristic (ROC) curves were conducted to assess the clinical value of Risk Score. Moreover, RNA-Seq date of OV patient derived from Gene Expression Omnibus (GEO, GSE32062) and the International Cancer Genome Consortium (ICGC) database (ICGC-AU), verifying the robustness of the Risk Score via Kaplan-Meier and ROC analysis.Pathway features were performed by gene set enrichment analysis and single sample gene set enrichment analysis. Finally, Risk Score in terms of chemotherapy drug sensitivity and immunotherapy suitability was also evaluated in different groups. RESULTS: 9-gene composition Risk Score system was finally determined by COX and LASSO COX analysis. Patients in the low Risk Score group possessed improved prognostic status, immune activity. PI3K pathway activity was increased in the high Risk Score group. In the chemotherapy drug sensitivity analysis, we found that the high Risk Score group might be more suitable for treatment with PI3K inhibitors Taselisib and Pictilisib. In addition, we found that patients in the low-risk group responded better to immunotherapy. CONCLUSION: Risk Score of 9-gene composition of PCD signature possesses promising clinical potential in OV prognosis, immunotherapy, immune microenvironment activity, and chemotherapeutic drug selection, and our study provides the basis for an in-depth investigation of the PCD mechanism in OV.
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CD8 + T-Cell-Related Genes: Deciphering Their Role in the Pancreatic Adenocarcinoma TME and Their Effect on Prognosis.
BACKGROUND: Because of the unique tumor microenvironment (TME), immunotherapy and targeted therapies have shown limited efficacy in treating pancreatic adenocarcinoma (PAAD). CD8 + T cells play crucial roles in regulating the TME in PAAD; therefore, exploring the function of CD8 + T-cell-related genes (CD8RGs) in PAAD has high potential clinical value and could provide a comprehensive understanding of the microenvironment of PAAD. METHODS: We employed the weighted gene coexpression network analysis and CIBERSORT algorithms to assess PAAD transcriptome data from The Cancer Genome Atlas (TCGA) dataset and identify modules strongly associated with CD8 + T cell infiltration. Using least absolute shrinkage and selection operator regression analysis and Kaplan-Meier curves, we developed a prognostic risk score model for patients with PAAD. We validated this model using single-cell and transcriptome datasets obtained from the Gene Expression Omnibus (GEO). We also examined the correlations between the risk score and factors such as the TME, clinical characteristics, and tumor mutation burden (TMB). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed on differentially expressed genes between the high- and low-risk groups. In addition, the Tumor Immune Dysfunction and Exclusion website and "pRRophetic" R package were used to predict response to immunotherapy and chemotherapy in the high- and low-risk groups, respectively. Finally, we analyzed the expressions of hub genes at the cellular level with quantitative real-time PCR. RESULTS: A risk model based on five CD8RGs was established and validated using TCGA and GEO datasets. The low-risk group exhibited significantly longer overall and progression-free survival. A positive correlation between the TMB and the risk score was observed. The TME analysis revealed a significant correlation between the risk score and immune function, as well as immune checkpoints. The expression of hub genes was significantly correlated with the infiltration level of CD8 + T cells. The high-risk group responded better to immunotherapy, paclitaxel, cisplatin, mitomycin C, afatinib (BIBW2992), and gefitinib. In contrast, the low-risk group showed higher sensitivity to sunitinib, MK.2206, palbociclib (PD.0332991), and axitinib. Compared with that in normal pancreatic epithelial cells, the expression levels of BCL11A, PHOSPHO1, and GNG7 were significantly decreased, while those of KLK11 and VCAM1 were significantly increased in pancreatic tumor cells. CONCLUSIONS: CD8RGs play an important role in regulating the TME of PAAD. Five hub genes-BCL11A, KLK11, GNG7, PHOSPHO1, and VCAM1-are closely associated with the prognosis of PAAD patients, providing new references for the exploration of biomarkers. Furthermore, our findings offer novel insights for clinical decision-making.
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Single-cell RNA sequencing reveals hemocyte heterogeneity, differentiation trajectories, and viral tropism in shrimp (Macrobrachium rosenbergii) infected with decapodiridovirus litopenaeus1.
Decapodiridovirus litopenaeus1 (DIV1) is a highly pathogenic virus threatening crustacean aquaculture. Hemocytes, the primary immune cells in shrimp, play crucial roles in host defense, yet their transcriptional heterogeneity and differentiation dynamics under viral infection remain poorly understood. Here, we characterize hemocyte subpopulations in Macrobrachium rosenbergii before and after DIV1 infection at single-cell resolution. We identified 12 distinct hemocyte clusters with unique molecular signatures. DIV1 infection induced significant shifts in hemocyte composition, with clusters 0, 5, 6, and 8 expanding, while clusters 9 and 10 exhibited resistance. Clusters 0, 5, and 8 were highly susceptible, showing elevated viral gene expression. Pseudo-time analysis revealed that DIV1 accelerates hemocyte differentiation, driving prohemocytes and semi-granulocytes toward terminally differentiated granulocytes and hyalinocytes, particularly the immune-active HC4 subpopulation. Functional enrichment analysis showed that susceptible hemocytes were associated with viral processes, oxidative stress, and phagocytosis, while resistant clusters exhibited distinct immune signatures. Furthermore, knockdown experiments confirmed the antiviral roles of PPO2, RAB11B, LAMP1, and Dorsal, as their silencing led to increased viral loads, higher major capsid protein (MCP) levels, and reduced shrimp survival. Taken together, our study provides the first single-cell resolution atlas of shrimp hemocytes under DIV1 infection, revealing their transcriptional heterogeneity, differentiation trajectories, and immune responses. These findings offer novel insights into shrimp antiviral immunity and lay the foundation for disease-resistant breeding and immunostimulatory strategies in aquaculture.IMPORTANCEDIV1 is a highly pathogenic virus threatening crustacean aquaculture, causing severe economic losses. Hemocytes in shrimp play crucial roles in antiviral defense, yet their diversity, differentiation, and responses to viral infection remain poorly understood. In this study, we employed single-cell RNA sequencing to comprehensively characterize hemocyte subpopulations in Macrobrachium rosenbergii before and after DIV1 infection. We identified 12 transcriptionally distinct hemocyte clusters and revealed significant changes in hemocyte composition following infection. Notably, we discovered that specific clusters (0, 5, and 8) were highly susceptible to DIV1, while others (9 and 10) exhibited resistance. Additionally, we reconstructed hemocyte differentiation trajectories and found that DIV1 infection drives hematopoiesis, accelerating the transition of progenitor cells into terminally differentiated immune-active hemocytes. Functional analysis highlighted key antiviral effectors, including PPO2, RAB11B, LAMP1, and Dorsal. These findings provide novel insights into shrimp antiviral immunity and viral pathogenesis, offering potential targets for disease-resistant breeding and immunostimulatory interventions.
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Integrative analyses identify CD73 as a prognostic biomarker and immunotherapeutic target in intrahepatic cholangiocarcinoma.
BACKGROUND: CD73 promotes progression in several malignancies and is considered as a novel immune checkpoint. However, the function of CD73 in intrahepatic cholangiocarcinoma (ICC) remains uncertain. In this study, we aim to investigate the role of CD73 in ICC. METHODS: Multi-omics data of 262 ICC patients from the FU-iCCA cohort were analyzed. Two single-cell datasets were downloaded to examine the expression of CD73 at baseline and in response to immunotherapy. Functional experiments were performed to explore the biological functions of CD73 in ICC. The expression of CD73 and HHLA2 and infiltrations of CD8 + , Foxp3 + , CD68 + , and CD163 + immune cells were evaluated by immunohistochemistry in 259 resected ICC samples from Zhongshan Hospital. The prognostic value of CD73 was assessed by Cox regression analysis. RESULTS: CD73 correlated with poor prognosis in two ICC cohorts. Single-cell atlas of ICC indicated high expression of CD73 on malignant cells. TP53 and KRAS gene mutations were more frequent in patients with high CD73 expression. CD73 promoted ICC proliferation, migration, invasion, and epithelial-mesenchymal transition. High CD73 expression was associated with a higher ratio of Foxp3 + /CD8 + tumor-infiltrating lymphocytes (TILs) and CD163 + /CD68 + tumor-associated macrophages (TAMs). A positive correlation between CD73 and CD44 was observed, and patients with high CD73 expression showed elevated expression of HHLA2. CD73 expression in malignant cells was significantly upregulated in response to immunotherapy. CONCLUSIONS: High expression of CD73 is associated with poor prognosis and a suppressive tumor immune microenvironment in ICC. CD73 could potentially be a novel biomarker for prognosis and immunotherapy in ICC.
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CXCR4 expression is associated with proneural-to-mesenchymal transition in glioblastoma.
Glioblastoma (GBM) is the most common primary intracranial malignant tumor and consists of three molecular subtypes: proneural (PN), mesenchymal (MES) and classical (CL). Transition between PN to MES subtypes (PMT) is the glioma analog of the epithelial-mesenchymal transition (EMT) in carcinomas and is associated with resistance to therapy. CXCR4 signaling increases the expression of MES genes in glioma cell lines and promotes EMT in other cancers. RNA sequencing (RNAseq) data of PN GBMs in The Cancer Genome Atlas (TCGA) and secondary high-grade gliomas (HGGs) from an internal cohort were examined for correlation between CXCR4 expression and survival as well as expression of MES markers. Publicly available single-cell RNA sequencing (scRNAseq) data was analyzed for cell type specific CXCR4 expression. These results were validated in a genetic mouse model of PN GBM. Higher CXCR4 expression was associated with significantly reduced survival and increased expression of MES markers in TCGA and internal cohorts. CXCR4 was expressed in immune and tumor cells based on scRNAseq analysis. Higher CXCR4 expression within tumor cells on scRNAseq was associated with increased MES phenotype, suggesting a cell-autonomous effect. In a genetically engineered mouse model, tumors induced with CXCR4 exhibited a mesenchymal phenotype and shortened survival. These results suggest that CXCR4 signaling promotes PMT and shortens survival in GBM and highlights its inhibition as a potential therapeutic strategy.
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WT1-AS acts as a tumor suppressor in cervical cancer via OSR2-mediated transcriptional activation.
BACKGROUND: Cervical cancer (CESC) remains a major global health burden, and its molecular mechanisms are not fully understood. Long non-coding RNAs (lncRNAs) have emerged as critical regulators in tumor biology. Among them, Wilms tumor 1 antisense RNA (WT1-AS) has been implicated in several cancers, but its role in CESC is largely unknown. Therefore, this study aimed to investigate the expression pattern, prognostic significance, biological function, and upstream transcriptional regulation of WT1-AS in CESC. METHODS: We performed a comprehensive analysis integrating The Cancer Genome Atlas (TCGA) pan-cancer and CESC datasets to examine the expression profile and prognostic relevance of WT1-AS. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and single-cell RNA sequencing analyses were conducted to explore its biological functions. Functional assays, including Western blotting, flow cytometry, and xenograft mouse models, were performed to validate the effects of WT1-AS on apoptosis and tumor growth. Upstream transcriptional regulation was investigated using transcription factor prediction, co-expression analysis, and luciferase reporter assays. RESULTS: WT1-AS was significantly dysregulated across multiple cancers and correlated with poor prognosis in several tumor types. In CESC, WT1-AS was primarily expressed in malignant epithelial cells and fibroblasts and was functionally enriched in apoptosis- and extracellular matrix-related pathways. Overexpression of WT1-AS promoted apoptosis, as evidenced by increased cleaved-caspase3 and cleaved-PARP expression, and suppressed tumor growth in vivo. Mechanistically, odd-skipped related transcription factor 2 (OSR2) was identified as a direct transcriptional regulator of WT1-AS. Overexpression of OSR2 enhanced apoptosis, and co-overexpression with WT1-AS further amplified pro-apoptotic effects. CONCLUSIONS: Our findings reveal that WT1-AS functions as a tumor suppressor in CESC by promoting apoptosis and identify OSR2 as a novel upstream regulator. The WT1-AS/OSR2 axis may have biological and potential prognostic relevance in CESC, although its clinical applicability requires further validation.
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SCALPEL: A pipeline for processing large-scale spatial transcriptomics data.
Spatial transcriptomics enables the precise mapping of gene expression patterns within tissue architecture, offering unprecedented insights into cellular interactions, tissue heterogeneity, and disease pathology that are unattainable with traditional transcriptomic approaches. We present a tool for processing spatial transcriptomics data, SCALPEL (Spatial Cell Analysis, Labeling, Processing, and Expression Linking). SCALPEL is specifically designed to support the analysis of large, atlas-level datasets. Our new workflow features advanced 3D segmentation optimized for dense and heterogeneous tissues, refined filtering criteria, and transcriptome-based doublet detection to remove low-quality or artifactual cells. Cell type label transfer from existing taxonomies is further improved through updated filtering thresholds. Spatial domain detection is incorporated to capture local transcriptomic organization, and tissue sections are registered to the Allen Mouse Brain Common Coordinate Framework version 3 (CCFv3) for precise anatomical alignment. Genome-wide expression imputation from single-cell RNA-sequencing (scRNAseq) further enriches the dataset. Crucially, we benchmark the performance of this updated pipeline against a previously published version of our whole-mouse-brain (WMB) dataset (Yao et al., 2023b), demonstrating substantial improvements in cell number, expression profile clarity, and spatial registration. These advances provide a robust foundation for downstream spatial analyses and set a new standard for large-scale spatial transcriptomics studies.
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Thyroid hormone deprivation creates an immunological signature in the mouse liver, involving Kupffer cell presentation as the mouse ages.
PURPOSE: Aging is associated with an increased prevalence of chronic liver diseases suggesting impaired immune and metabolic function. In addition, thyroid hormone (TH) impacts liver physiology and TH deprivation or excess negatively affect organ maintenance. However, whether age-dependent consequences of TH alterations are reflected in a liver-specific adaptation is unknown so far. The present study aimed to characterize the impact of TH deprivation or excess on the liver transcriptome during aging. METHODS: Five- and 21-month-old male C57BL/6 mice were exposed either to chronic TH deprivation or to chronic TH excess and compared to control treatment by microarray-based liver transcriptome analysis. RESULTS: Significant roles of both TH state and age became obvious: Bioinformatic analysis of the liver transcriptome data revealed an age-dependent immune signature by chronic TH deprivation, an age-dependent immune and metabolic signature independent of exogenous TH modulation, as well as an age-dependent metabolic signature by chronic TH excess. Published data of single cell transcriptomic atlas characterizing aging tissues in the mouse were compared with our data and revealed Kupffer cell presentation in the immunological signature by TH deprivation during aging. Literature data for four prominent differentially expressed genes, namely C1qb, C3ar1, Ctss, and Msr1, revealed that the complement system, extracellular matrix remodelling, as well as the proinflammatory phenotype of Kupffer cells are altered by TH deprivation during aging. CONCLUSION: In conclusion, our study illuminates the interplay between TH deprivation, aging, and liver transcriptome signatures, highlighting potential implications for immune function and tissue maintenance, particularly through the modulation of Kupffer cell presentation.
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Spatiotemporal Evolution of Malignant Hepatocyte Clones Unveils Immune Evasion Features and Therapeutic Vulnerabilities in Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC), a highly lethal disease often developing in the context of chronic liver disease, is marked by high relapse rates and low 5-year survival. To investigate the multicellular ecosystem and molecular features of hepatocarcinogenesis and progression, a comprehensive analysis integrating single-cell and spatial transcriptomics was conducted. Significant alterations were observed in various cell types, notably an increase in liver parenchymal and endothelial cells, which play critical roles in tissue repair and angiogenesis. Scissor+ cells, predominantly hepatocytes, were identified as potentially evolving into malignant cells with poor prognosis and enhanced immune evasion capabilities. Key genes associated with Scissor+ cells exhibited potential as cancer prognostic markers. Additionally, the disruption of cellular communication networks during malignant progression revealed the evolution of hepatocytes into cancerous phenotypes. The enhanced signaling pathways, such as MDK-SDC4 and COL4A-SDC, were identified as pivotal in driving the malignant transformation of hepatocytes. This transformative process, wherein Scissor+ cells acquire malignant features, highlights novel mechanisms of cancer progression. These findings provide deeper insights into hepatocarcinogenesis and offer potential avenues for targeted and personalized therapeutic strategies.