Anti-VEGF treatment potentiates ICB responses through a BAFF and IL-12-dependent reprogramming of the TME
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ABSTRACT:
PROVIDER: PRJNA1197972 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31707293_1.fastq.gz | Fastqsanger.gz | |||
| SRR31707293_2.fastq.gz | Fastqsanger.gz | |||
| SRR31707294_1.fastq.gz | Fastqsanger.gz | |||
| SRR31707294_2.fastq.gz | Fastqsanger.gz | |||
| SRR31707295_1.fastq.gz | Fastqsanger.gz |
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Project description:Anti-VEGF treatment has shown clinical activity in combination with checkpoint inhibitor therapy, but the exact mechanism is not known. We show that adding VEGF blockade to the ICB combination of anti-CTLA4 + anti-PD-L1 in cholangiocarcinoma unleashed a therapeutic efficacy driven through a novel multimodal mechanism dependent on BAFF production by T and myeloid cells, leading to a BAFF-dependent proinflammatory B cell response characterized by Germinal center B cell and plasma cell expansion, as well as IL-12 production. Using single cell RNA sequencing (scRNA-Seq) of paired pre- and post-treatment tumor biopsy samples from patients treated with anti-CTLA4, anti-PD-L1 and anti-VEGF, we characterized the treatment-associated immunological changes.
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Project description:The purpose of the study was to identify downstream gene targets regulated by a new alternative splice of BAFF (B-Cell Activating factor belonging to the TNF Family) that we called Delta4-BAFF (because it characterized by an alternative splice of exon 4). To do this we used human burkitt's lymphoma cell line (RAMOS) stably transfected with Delta4-BAFF or stably transfected with Delta4-BAFF mutated on its N-glycosylation site (Delta4-BAFF-N124D). One control was used : RAMOS stably transfected with empty vector (pIRES2-GFP from Clontech)
2012-09-28 | E-MEXP-3595 | biostudies-arrayexpress
Project description:Tumor-infiltrating Tregs were FACS sorted using their YFP signal from processed SB1 tumors implanted in Kdr(fl/fl)xFoxp3(yfp-cre) or Kdr(+/+)xFoxp3(yfp-cre) mice, fro which RNA was isolated for Nanostring analysis usig the Murine Cancer Immune Profiling Panel Anti-VEGF treatment has shown clinical activity in combination with checkpoint inhibitor therapy, but the exact mechanism is not known. We show that adding VEGF blockade to the ICB combination of anti-CTLA4 + anti-PD-L1 in cholangiocarcinoma unleashed a therapeutic efficacy driven through a novel multimodal mechanism dependent on BAFF production by T and myeloid cells, leading to a BAFF-dependent proinflammatory B cell response characterized by Germinal center B cell and plasma cell expansion, as well as IL-12 production. The mechanism culminates in a BAFF and IL-12-dependent expansion and rewiring of Tregs towards an anti-tumor Th-1-like fragile state. We translated this approach to the clinic with encouraging outcomes following an interim analysis of the first six CCA patients. Using paired PBMC, serum and tumor biopsy samples from patients treated with anti-CTLA4, anti-PD-L1 and anti-VEGF, we again observed treatmentassociated immunological changes characterized by Treg expansion and rewiring towards fragile and unstable states and a proinflammatory cytokine profile including elevated BAFF and IL-12 levels. Correlating immune changes with overall survival identified BAFF and IL-12 as potential biomarkers of treatment response. Finally, we explored the direct effect of VEGFR2 signaling on Treg transcriptional programming. Fragile and unstable Tregs showed diminished VEGF/VEGFR2 signaling. A mouse model genetically ablating VEGFR2 expression on Tregs led to diminished suppressive function and delayed tumor growth, an effect that was further enhanced by ICB therapy.
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Project description:Emerging clinical evidence points to a function for B cell activating factor (BAFF) in pregnancy. However, a direct role for BAFF-axis members including BAFF, the closely related a proliferation-inducing ligand (APRIL), and their respective receptors in pregnancy has not been examined. This study demonstrates that loss of BAFF results in decreased inflammatory responsiveness and decreased susceptibility to inflammation-induced preterm birth (PTB). In contrast, loss of APRIL increases inflammatory responsiveness and susceptibility to PTB. Consistent with overlapping receptor utilization by BAFF and APRIL, deletion of BAFF-axis receptors is not sufficient to modify susceptibility to PTB. Critically, therapeutic administration of BAFF/APRIL monoclonal antibodies or recombinant proteins is sufficient to manipulate susceptibility to inflammation-induced PTB. Further, macrophages are identified as the principle BAFF producing immune cells at the maternal-fetal interface and BAFF and APRIL divergently manipulate macrophage gene expression and inflammatory function. Genes linked to labor initiation are upregulated in WT and APRIL deficient macrophages while downregulated in BAFF deficient macrophages and correlate with myeloid gene expression in human placental samples during labor. Thus, BAFF and APRIL play important, but divergent, counterregulatory inflammatory roles in pregnancy and provide new therapeutic targets for mitigating the risk of PTB.
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Project description:Immune checkpoint blockade (ICB) has revolutionized cancer treatment, but the therapeutic response is highly heterogeneous. A potential mode of resistance is tumor-intrinsic mechanisms leading to an immunosuppressive tumor microenvironment. However, the underlying interactive network remains elusive and the generalizable biomarkers and targeting strategies are still lacking. Here, we uncovered the potential of plasma S100 calcium-binding protein A1 (S100A1) in determining ICB efficacy based on liquid biopsy of patients with lung cancer. Muti-omics and functional studies suggested that tumor-intrinsic S100A1 expression correlates with an immunologically cold TME and resistance to ICB. Mechanistic investigations demonstrated that interfering with tumor-intrinsic S100A1/ubiquitin-specific protease 7/p65/granulocyte-macrophage colony-stimulating factor (GM-CSF) modulatory axis could potentiate an inflamed TME via promoting M1-like macrophage polarization and T cell function. GM-CSF priming was sufficient to enhance ICB response in tumors with high S100A1 expression. These findings defined S100A1 as a potential biomarker and a novel synergistic target for cancer immunotherapy.
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Project description:Identify genes which are induced in wild type B cells under antigenic stimuli, anti-IgM vs pro-survival stimuli, BAFF. Also find the differential expressed genes which are distinct from in co-stimulated conditions. RNAseq analysis of wild type primary B cells stimulated with anti-IgM alone, BAFF alone, or co-stimulated with both anti-IgM and BAFF for 8 and 30 hours
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