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Single-cell atlas profiling revealed cellular characteristics and dynamic changes after PD-1 blockade therapy of brain metastases from laryngeal squamous cell carcinoma.
Brain metastasis (BM) in laryngeal squamous cell carcinoma (LSCC) is uncommon but prognosis is poor. Anti-PD-1 immunotherapy benefits some advanced LSCC cases, yet its efficiency is limited by tumor complexity. We analyzed paired metastatic tumor samples from before and after immunotherapy using single-cell RNA sequencing (scRNA-seq), along with a primary LSCC dataset and bulk RNA sequencing. This identified changes post-immunotherapy and revealed differences in single-cell transcriptomes among LSCC, primBM, and neoBM. Our findings show that anti-PD-1 treatment suppresses metastasis-promoting pathways like VEGF and EMT in cancer cells, and alters immune cell functions. Notably, it upregulates T cell activation, leading to CD8 T cell exhaustion from excess heat shock proteins, notably HSPA8. However, CD8 T cell cytotoxic functions improve post-treatment. In myeloid cells, anti-PD-1 therapy enhances antigen presentation and promotes a proinflammatory shift post-metastasis. Additionally, NUPR1 is linked to BM in LSCC, and NEAT1 is a potential metastatic cancer cell cycle participant. Our study provides insights into cancer heterogeneity and the impact of PD-1 immunotherapy on metastasis, aiding precise diagnosis and prognosis.
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MICA+ Tumor Cell Upregulated Macrophage-Secreted MMP9 via PROS1-AXL Axis to Induce Tumor Immune Escape in Advanced Hepatocellular Carcinoma (HCC).
BACKGROUND: tumor-associated macrophages (TAMs) constitute a significant proportion of non-cancerous cells within the intricate tumor microenvironment (TME) of hepatocellular carcinoma (HCC). Understanding the communication between macrophages and tumor cells, as well as investigating potential signaling pathways, holds promise for enhancing therapeutic responses in HCC. METHODS: single-cell RNA-sequencing data and bulk RNA-sequencing data were derived from open source databases Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Through this analysis, we elucidated the interactions between MICA+ tumor cells and MMP9+ macrophages, primarily mediated via the PROS1-AXL axis in advanced HCC. Subsequently, we employed a range of experimental techniques including lentivirus infection, recombinant protein stimulation, and AXL inhibition experiments to validate these interactions and unravel the underlying mechanisms. RESULTS: we presented a single-cell atlas of advanced HCC, highlighting the expression patterns of MICA and MMP9 in tumor cells and macrophages, respectively. Activation of the interferon gamma (IFN-γ) signaling pathway was observed in MICA+ tumor cells and MMP9+ macrophages. We identified the existence of an interaction between MICA+ tumor cells and MMP9+ macrophages mediated via the PROS1-AXL axis. Additionally, we found MMP9+ macrophages had a positive correlation with M2-like macrophages. Subsequently, experiments validated that DNA damage not only induced MICA expression in tumor cells via IRF1, but also upregulated PROS1 levels in HCC cells, stimulating macrophages to secrete MMP9. Consequently, MMP9 led to the proteolysis of MICA. CONCLUSION: MICA+ HCC cells secreted PROS1, which upregulated MMP9 expression in macrophages through AXL receptors. The increased MMP9 activity resulted in the proteolytic shedding of MICA, leading to the release of soluble MICA (sMICA) and the subsequent facilitation of tumor immune escape.
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hAECs restore follicular development in premature ovarian insufficiency via IGFBP2/IGF1R-mediated intercellular communication.
BACKGROUND: Premature ovarian insufficiency (POI) is defined by ovarian dysfunction and consequent decreased fertility. While follicular depletion is an acknowledged factor, dynamic changes in follicular subpopulations and single-cell-level niche remodeling remains largely unexplored. Human amniotic epithelial cells (hAECs) represent a promising regenerative approach for restoring ovarian function; however, the underlying mechanism in promoting follicular development remains unclear. METHODS: We established a chemotherapy-induced POI mouse model and conducted single-nucleus RNA sequencing (snRNA-seq) to systematically characterize ovarian cellular heterogeneity, residual follicular development, and ovarian microenvironmental alteration. A human-derived cell projection model was established to track the distribution of transplanted hAECs. Furthermore, the functional role of IGF1R signaling in granulosa cells was validated using both in vitro culture assays and in vivo interventions. RESULTS: We identified eight distinct ovarian cell types and uncovered stage-specific injury patterns: acute chemotherapy exposure induced massive loss of granulosa cells and oocytes, while the chronic phase was characterized by fibrotic accumulation and immune infiltration. Furthermore, residual follicles exhibited aberrant development trajectories and compromised progression, primarily due to disrupted granulosa cells -oocytes communication. Notably, hAEC transplantation significantly enhanced follicle survival, partially attenuated fibrosis and promoted ovarian structural restoration. Mechanistically, hAECs-derived IGFBP2 regulated IGF1R expression in granulosa cells, thereby reactivating the Akt/FoxO3A signaling pathway and downregulating the senescence marker P21. CONCLUSIONS: This study presents a time-resolved snRNA-seq atlas capturing both acute and chronic injury phases in a chemotherapy-induced POI model, combined with a human-mouse projection approach to track transplanted hAECs in damaged ovaries. Our study establishes a novel cell-based therapeutic strategy for partial ovarian functional recovery, in which hAEC-derived IGFBP2 restores granulosa cell function and intercellular communication by regulating the IGF1R/Akt/mTOR signaling axis.
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Cell Type- and Age-Specific Expression of lncRNAs across Kidney Cell Types.
KEY POINTS: We constructed a single-cell long noncoding RNA atlas of various tissues, including normal and aged kidneys. We identified age- and cell type–specific expression changes of long noncoding RNAs in kidney cells. BACKGROUND: Accumulated evidence demonstrates that long noncoding RNAs (lncRNAs) regulate cell differentiation and homeostasis, influencing kidney aging and disease. Despite their versatility, the function of lncRNA remains poorly understood because of the lack of a reference map of lncRNA transcriptome in various cell types. METHODS: In this study, we used a targeted single-cell RNA sequencing method to enrich and characterize lncRNAs in individual cells. We applied this method to various mouse tissues, including normal and aged kidneys. RESULTS: Through tissue-specific clustering analysis, we identified cell type–specific lncRNAs that showed a high correlation with known cell-type marker genes. Furthermore, we constructed gene regulatory networks to explore the functional roles of differentially expressed lncRNAs in each cell type. In the kidney, we observed dynamic expression changes of lncRNAs during aging, with specific changes in glomerular cells. These cell type– and age-specific expression patterns of lncRNAs suggest that lncRNAs may have a potential role in regulating cellular processes, such as immune response and energy metabolism, during kidney aging. CONCLUSIONS: Our study sheds light on the comprehensive landscape of lncRNA expression and function and provides a valuable resource for future analysis of lncRNAs (https://gist-fgl.github.io/sc-lncrna-atlas/).
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The Hydractinia cell atlas reveals cellular and molecular principles of cnidarian coloniality.
Coloniality is a widespread growth form in cnidarians, tunicates, and bryozoans, among others. Colonies function as single physiological units despite their modular structure of zooids and supporting tissues. A key question is how structurally and functionally distinct colony parts are generated. In the cnidarian Hydractinia symbiolongicarpus, colonies consist of zooids (polyps) interconnected by stolons attached to the substrate. Using single-cell transcriptomics, we profiled ~200,000 Hydractinia cells, including stolons and two polyp types, identifying major cell types and their distribution across colony parts. Distinct colony parts are primarily characterised by unique combinations of shared cell types and to a lesser extent by part-specific cell types. We identified cell type-specific transcription factors (TFs) and gene sets expressed within these cell types. This suggests that cell type combinations and occasional innovations drive the evolution of coloniality in cnidarians. We uncover a novel stolon-specific cell type linked to biomineralization and chitin synthesis, potentially crucial for habitat adaptation. Additionally, we describe a new cell type mediating self/non-self recognition. In summary, the Hydractinia cell atlas provides insights into the cellular and molecular mechanisms underpinning coloniality.
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Exploring Functionally Enhanced BLP-Trained Macrophage Subpopulations in S. Aureus Infection: Underlying Mechanisms and Therapeutic Significance.
Tolerance to bacterial lipoprotein (BLP) is an evolved protective mechanism characterized by an enhanced resistance of BLP-trained macrophages to microbial infection. However, the underlying mechanisms are not fully understood, and their potential for translational clinical application needs further evaluation. In the present study, through single-cell RNA sequencing (scRNA-seq), transcriptomic profiles in both naïve and BLP-trained bone marrow-derived macrophages (BMDMs) during Staphylococcus aureus infection are analyzed, and 13 distinct BMDM subpopulations are identified. Notably, BLP-trained tolerance initiates the emergence of two novel BMDM subpopulations, C5 and C7, characterized by increased antibacterial gene expression and enhanced anti-inflammatory and antioxidative stress abilities. Moreover, BLP-trained BMDMs demonstrate activation of the NRF2 signaling pathway, thereby augmenting an antioxidative stress response and mitigating oxidative stress-induced cell damage and ferroptosis, while undergoing metabolic reprogramming characterized by enhanced glycolysis and oxidative phosphorylation pathways, together with increased anti-inflammatory metabolites. Critically, in vivo adoptive transfer of BLP-trained BMDMs protects mice against sepsis-associated lethality by attenuating systemic inflammatory response, accelerating bacterial clearance, and alleviating organ damage. Collectively, the present study presents a single-cell atlas of murine BMDMs at rest and under S. aureus infection following BLP training, which reveals novel mechanisms of BLP training-altered macrophage immunity and identifies macrophage subpopulations responsible for an enhanced resistance to infection, thus offering new preventive and therapeutic strategies for sepsis.
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Targeting Lymphotoxin Beta and Paired Box 5: a potential therapeutic strategy for soft tissue sarcoma metastasis.
BACKGROUND: Soft tissue sarcomas (STS) has a high rate of early metastasis. In this study, we aimed to uncover the potential metastasis mechanisms and related signaling pathways in STS with differentially expressed genes and tumor-infiltrating cells. METHODS: RNA-sequencing (RNA-seq) of 261 STS samples downloaded from the Cancer Genome Atlas (TCGA) database were used to identify metastasis-related differentially expressed immune genes and transcription factors (TFs), whose relationship was constructed by Pearson correlation analysis. Metastasis-related prediction model was established based on the most significant immune genes. CIBERSORT algorithm was performed to identify significant immune cells co-expressed with key immune genes. The GSVA and GSEA were performed to identify prognosis-related KEGG pathways. Ultimately, we used the Pearson correlation analysis to explore the relationship among immune genes, immune cells, and KEGG pathways. Additionally, key genes and regulatory mechanisms were validated by single-cell RNA sequencing and ChIP sequencing data. RESULTS: A total of 204 immune genes and 12 TFs, were identified. The prediction model achieved a satisfactory effectiveness in distant metastasis with the Area Under Curve (AUC) of 0.808. LTB was significantly correlated with PAX5 (P < 0.001, R = 0.829) and hematopoietic cell lineage pathway (P < 0.001, R = 0.375). The transcriptional regulatory pattern between PAX5 and LTB was validated by ChIP sequencing data. CONCLUSIONS: We hypothesized that down-regulated LTB (immune gene) modulated by PAX5 (TF) in STSs may have the capability of inducing cancer cell metastasis in patients with STS.
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An immunophenotype-coupled transcriptomic atlas of human hematopoietic progenitors.
Analysis of the human hematopoietic progenitor compartment is being transformed by single-cell multimodal approaches. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) enables coupled surface protein and transcriptome profiling, thereby revealing genomic programs underlying progenitor states. To perform CITE-seq systematically on primary human bone marrow cells, we used titrations with 266 CITE-seq antibodies (antibody-derived tags) and machine learning to optimize a panel of 132 antibodies. Multimodal analysis resolved >80 stem, progenitor, immune, stromal and transitional cells defined by distinctive surface markers and transcriptomes. This dataset enables flow cytometry solutions for in silico-predicted cell states and identifies dozens of cell surface markers consistently detected across donors spanning race and sex. Finally, aligning annotations from this atlas, we nominate normal marrow equivalents for acute myeloid leukemia stem cell populations that differ in clinical response. This atlas serves as an advanced digital resource for hematopoietic progenitor analyses in human health and disease.
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Characterization of the tumour microenvironment phenotypes in malignant tissues and pleural effusion from advanced osteoblastic osteosarcoma patients.
PURPOSE: Malignant pleural effusion (MPE) is an adverse prognostic factor in patients with osteoblastic osteosarcoma; however, the cellular contexts of MPE are largely unknown. EXPERIMENTAL DESIGN: We performed single-cell RNA-sequencing (scRNA-seq) on 27 260 cells from seven MPE samples and 91 186 cells from eight osteosarcoma tissues, including one recurrent, one lung metastasis and six primary tumour (PT) samples, to characterize their tumour microenvironment. RESULTS: Thirteen main cell groups were identified in osteosarcoma tumour and MPE samples. Immune cells dominate the cellular contexts in MPE with more T/NK cells and less osteoclasts compared to PT samples. Of T/NK cells, CD8+ GNLY+ , CD8+ KLRC2+ T cells and FCGR3A+ NK cells were enriched in MPE but CD4+ FOXP3+ Tregs were enriched in PT samples. Naïve IGHD+ B and immune regulatory IGHA1+ B cells were largely identified in MPE, whereas bone metabolism-related CLEC11A+ B cells were significantly enriched in osteosarcoma PT. M2-type TAMs, including CLEC11A_TAM, C1QC_TAM and Prolif_TAMs, among myeloid cells were enriched in PT, which may suppress cytotoxicity activities of T cells through multiple ligand-receptor interactions. Mature LAMP3+ DCs were transformed from CD1C+ DC and CLEC9A+ DC sub-clusters when exposure to tumour alloantigens, which may improve T cell cytotoxicity activities on tumour cells under anti-PD-L1 treatments. In further, immune cells from MPE usually present up-regulated glycolysis and down-regulated oxidative phosphorylation and riboflavin metabolism activities compared to those in PT samples. CONCLUSIONS: Our study provided a novel cellular atlas of MPE and PT in patients with advanced osteosarcoma, which may provide potential therapeutic targets in the future.
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RAC2 as a Tumor-Suppressive Biomarker Associated with T Cell Infiltration in Breast Cancer.
Background: RAC2 is critical in regulating the homeostasis of hematopoietic stem cells. Nonetheless, its role in breast cancer (BC) remains unclear, necessitating further investigation. Methods: The expression of RAC2 in BC and healthy tissues was acquired from The Cancer Genome Atlas. Its validity was further assessed using datasets from the gene expression omnibus database. The Tumor Immune Single-cell Hub database was used to collect and analyze the single-cell RNA sequencing datasets of BC. The diagnostic relevance of RAC2 was evaluated using receiver operating characteristic curves. Further assessment was carried out via enrichment analyses; Gene Set Analysis, immune scoring, single-cell sequencing, and immunohistochemical analysis were conducted to confirm the relationship between RAC2 expression and immune infiltration. Results: RAC2 expression was notably heightened in BC (p < 0.001). It was observed that a better prognosis was linked to heightened expression of RAC2 (p < 0.01), with the diagnostic efficacy of the marker noted to be good (area under the curve = 0.858). We found a lower percentage of protumor immune cells and a greater proportion of antitumor immune cells in the high RAC2. Our analysis revealed alterations in gene expression and an enriched network of immune pathways influenced by RAC2. Notably, cytotoxic genes, chemokines, chemokine receptors, immunostimulators, and immunosuppressive molecules positively correlated with RAC2 expression. RAC2 expression reliably predicted how patients would respond to two different therapeutic approaches in BC. Conclusions: The RAC2 was found to be a key biomarker in BC in the current study, demonstrating considerable potential as a prognostic and diagnostic marker. These results highlight the RAC2 potential to improve precision medicine strategies and treatment outcomes for patients with BC.