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Conserved transcriptional connectivity of regulatory T cells in the tumor microenvironment informs novel combination cancer therapy strategies [mouse]

ABSTRACT: While regulatory T (Treg) cells are traditionally viewed as professional suppressors of antigen presenting and effector T cells in both autoimmunity and cancer, recent findings of distinct Treg functions in tissue maintenance suggest that their regulatory purview extends to a wider range of cells and is broader than previously assumed. To elucidate tumoral Treg “connectivity” to diverse tumor-supporting accessory cell types, we explored immediate early changes in their single cell transcriptomes upon punctual Treg depletion in experimental lung cancer and injury-induced inflammation. Prior to any notable T cell activation and inflammation, fibroblasts, endothelial and myeloid cells exhibited pronounced changes in their gene expression in both cancer and injury settings. Factor analysis revealed shared Treg-dependent gene programs, foremost, prominent upregulation of VEGF signaling-related genes upon Treg deprivation in either setting, as well as in Treg-poor vs Treg-rich human lung adenocarcinomas. Accordingly, punctual Treg depletion combined with short-term VEGF blockade showed markedly improved control of PD-1 blockade-resistant lung adenocarcinoma progression in mice compared to the corresponding monotherapies, highlighting a promising factor-based querying approach to elucidating novel rational combination treatments of solid organ cancers.

ORGANISM(S): Mus musculus

PROVIDER: GSE202157 | GEO | 2023/05/01

REPOSITORIES: GEO

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Conserved transcriptional connectivity of regulatory T cells in the tumor microenvironment informs novel combination cancer therapy strategies [visium]

Project description:While regulatory T (Treg) cells are traditionally viewed as professional suppressors of antigen presenting and effector T cells in both autoimmunity and cancer, recent findings of distinct Treg functions in tissue maintenance suggest that their regulatory purview extends to a wider range of cells and is broader than previously assumed. To elucidate tumoral Treg “connectivity” to diverse tumor-supporting accessory cell types, we explored immediate early changes in their single cell transcriptomes upon punctual Treg depletion in experimental lung cancer and injury-induced inflammation. Prior to any notable T cell activation and inflammation, fibroblasts, endothelial and myeloid cells exhibited pronounced changes in their gene expression in both cancer and injury settings. Factor analysis revealed shared Treg-dependent gene programs, foremost, prominent upregulation of VEGF signaling-related genes upon Treg deprivation in either setting, as well as in Treg-poor vs Treg-rich human lung adenocarcinomas. Accordingly, punctual Treg depletion combined with short-term VEGF blockade showed markedly improved control of PD-1 blockade-resistant lung adenocarcinoma progression in mice compared to the corresponding monotherapies, highlighting a promising factor-based querying approach to elucidating novel rational combination treatments of solid organ cancers.

2023-05-03 | GSE215361 | GEO

Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis

Project description:We asked whether combining Notch and VEGF blockade would enhance suppression of tumor angiogenesis and growth, using the NGP neuroblastoma model. NGP tumors were engineered to express a Notch1 decoy construct (N1D), which restricts Notch signaling, and then treated with either the anti-VEGF antibody bevacizumab or vehicle. Combining Notch and VEGF blockade led to blood vessel regression, increasing endothelial cell apoptosis and disrupting pericyte coverage of endothelial cells. Combined Notch and VEGF blockade did not affect tumor weight, but did additively reduce tumor viability. Our results indicate that Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis, and show that concurrent blockade disrupts primary tumor vasculature and viability further than inhibition of either pathway alone. 6 neuroblastoma tumors were transfected with Notch1 decoy, 6 with Notch1 decoy and treated with bevacizumab, 6 tumors treated with bevacizumab, and 6 control tumors were profiled by human 133A 2.0 arrays

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Epigenetic profiling of OVA-specific CD8+ TILs from mice treated with control, anti-B7S1, anti-PD-1 or anti-B7S1+anti-PD-1 antibodies

Project description:Combinational blockade of B7S1 and PD-1 exhibits stronger anti-tumor efficacy than monotherapies. In order to further understand the mechanisms whereby blockade of B7S1 or PD-1 inhibits tumor growth, we conducted ATAC-seq analysis of OVA-specific CD8+ TILs from E.G7-bearing mice treated with control antibodies, anti-B7S1, anti-PD-1 monotherapy or combinational therapy.

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Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis

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Aging imparts cell-autonomous dysfunction to regulatory T cells during recovery from influenza pneumonia [RNA-seq]

Project description:Regulatory T (Treg) cells promote recovery from lung injury. Aging imparts cell-autonomous dysfunction to regulatory T cells during recovery from influenza pneumonia.

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Aging imparts cell-autonomous dysfunction to regulatory T cells during recovery from influenza pneumonia [DNA methylation/RRBS]

Project description:Regulatory T (Treg) cells promote recovery from lung injury. Aging imparts cell-autonomous dysfunction to regulatory T cells during recovery from influenza pneumonia.

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An integrated approach to profile lung tumor endothelial cell heterogeneity across species and models and to identify angiogenic candidates

Project description:Heterogeneity of lung tumor endothelial cell (TEC) phenotypes across patients, species (human/mouse) and models (in vivo/vitro) remains poorly inventoried at the single-cell-level. We single-cell RNA-sequenced 56,771 ECs from human/mouse (peri)-tumoral lung and cultured human lung TECs, detected 17 known and discovered 16 novel phenotypes, including TECs presumably regulating immune surveillance. We resolved the canonical tip TECs into a known migratory tip and a novel basement-membrane remodeling breach phenotype. Tip-TEC signatures correlated with patient-survival, and tip/breach TECs were most sensitive to VEGF-blockade. By similarity analysis, only tip-TECs were congruent across species/models and shared conserved markers. Integrated analysis of the scRNA-seq data with orthogonal multi-omics and meta-analysis data across different human tumors, validated by functional analysis, identified collagen-modification as angiogenic candidate pathway.

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MicroRNA-1 protects the endothelium in acute lung injury

Project description:Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), cause severe endothelial dysfunction in the lung and vascular endothelial growth factor (VEGF) is elevated in ARDS. We have found that the levels of a VEGF-regulated microRNA, microRNA-1 (miR-1) is reduced in the lung endothelium after acute injury. Pulmonary endothelial cell (EC)-specific overexpression of miR-1 protects the lung against cell death and barrier dysfunction in both murine and human models and increases the survival of mice after pneumonia-induced ALI. MiR-1 has an intrinsic protective effect in pulmonary and other types of ECs; it inhibits apoptosis and necroptosis pathways and decreases capillary leak by protecting adherens and tight junctions. Comparative gene expression analysis and RISC recruitment assays identified miR-1 targets in the context of injury, including phosphodiesterase 5A (PDE5A), angiopoetin-2 (ANGPT2), connector enhancer of kinase suppressor of ras 3 (CNKSR3) and TNF alpha induced protein 2 (TNFAIP2). We validated miR-1-mediated regulation of ANGPT2 in both mouse and human ECs and found that in a 119-patient pneumonia cohort, miR-1 correlated inversely with ANGPT2. These findings illustrate the novel role of miR-1 as a cytoprotective orchestrator of endothelial response to acute injury with prognostic and therapeutic potential.

2023-10-25 | GSE236263 | GEO

MicroRNA-1 protects the endothelium in acute lung injury

2023-10-25 | GSE239928 | GEO

Transcriptional Analysis of Foxp3+ Regulatory T Cells in Experimental Acute Lung Injury Resolution

Project description:These studies profiled the expression of mRNA in lung and spleen regulatory T cells in Foxp3EGFP mice during lipopolysaccharide-induced lung injury. Baseline, uninjured Lung Treg and Resolving Lung Tregs and Resolving Splenic Tregs were sorted (7 days after intratracheal instillation of LPS for Resolving conditions) and mRNAs differentially expressed (DE) between Control Lung Tregs, Resolving Lung Tregs and Resolving Splenic Tregs samples were identified using microarrays.

2019-02-12 | GSE104088 | GEO

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