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Intra-tumoral activation of endosomal TLR pathways reveals a distinct role for TLR3 agonist dependent type-1 interferons in shaping the tumor immune microenvironment

ABSTRACT: Intra-tumoral activation of endosomal TLR pathways reveals a distinct role for TLR3 agonist dependent type-1 interferons in shaping the tumor immune microenvironment

PROVIDER: PRJNA743864 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15043330.fastq.gz	Fastqsanger.gz
	SRR15043331.fastq.gz	Fastqsanger.gz
	SRR15043332.fastq.gz	Fastqsanger.gz
	SRR15043333.fastq.gz	Fastqsanger.gz
	SRR15043334.fastq.gz	Fastqsanger.gz

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Intra-Tumoral Activation of Endosomal TLR Pathways Reveals a Distinct Role for TLR3 Agonist Dependent Type-1 Interferons in Shaping the Tumor Immune Microenvironment.

Project description:Toll-like receptor (TLR) agonists have received considerable attention as therapeutic targets for cancer immunotherapy owing to their ability to convert immunosuppressive tumor microenvironments towards a more T-cell inflamed phenotype. However, TLRs differ in their cell expression profiles and intracellular signaling pathways, raising the possibility that distinct TLRs differentially influence the tumor immune microenvironment. Using single-cell RNA-sequencing, we address this by comparing the tumor immune composition of B16F10 melanoma following treatment with agonists of TLR3, TLR7, and TLR9. Marked differences are observed between treatments, including decreased tumor-associated macrophages upon TLR7 agonist treatment. A biased type-1 interferon signature is elicited upon TLR3 agonist treatment as opposed to a type-2 interferon signature with TLR9 agonists. TLR3 stimulation was associated with increased macrophage antigen presentation gene expression and decreased expression of PD-L1 and the inhibitory receptors Pirb and Pilra on infiltrating monocytes. Furthermore, in contrast to TLR7 and TLR9 agonists, TLR3 stimulation ablated FoxP3 positive CD4 T cells and elicited a distinct CD8 T cell activation phenotype highlighting the potential for distinct synergies between TLR agonists and combination therapy agents.

| S-EPMC8351420 | biostudies-literature

Molecular characterization of endosomal self RNA Rmrp-engaged TLR3 dimerization to prime innate activation

Project description:In this study, we demonstrate that endosome-localized self RNA Rmrp directly binds to TLR3 and induces TLR3 dimerization in the early endosome but does not interact with endosome-localized TLR7, TLR8, TLR9 or cytoplasmic RNA sensor RIG-I under homeostatic conditions. Cryo-EM structure of Rmrp-TLR3 complex reveals a novel lapped conformation of TLR3 dimer engaged by Rmrp, which is distinct from the activation mechanism by dsRNA and the specific structural feature at the 3'-end of Rmrp is critical for its functional interaction with TLR3. Furthermore, K42 residue of TLR3 is essential for binding to Rmrp and subsequent dimerization. Rmrp dissociates from TLR3 following endosomal acidification, generating a matured TLR3 dimer which is primed for innate recognition and activation. Myeloid-cell deficiency of Rmrp reduces TLR3 dimerization and attenuates TLR3-mediated antiviral responses against influenza A both in vitro and in vivo.

2025-04-01 | GSE159459 | GEO

Intra-tumoral activation of endosomal TLR pathways reveals a distinct role for TLR3 agonist dependent type-1 interferons in shaping the tumor immune microenvironment

2021-07-16 | GSE179449 | GEO

Molecular characterization of endosomal self RNA Rmrp-engaged TLR3 dimerization to prime innate activation

Project description:Molecular characterization of endosomal self RNA Rmrp-engaged TLR3 dimerization to prime innate activation

| PRJNA669002 | ENA

Phosphorylated TLR3 nuclear translocation in cancer cell promotes metastasis and chemoresistance

Project description:Aberrant expression and subcellular location of innate sensors in cancer cells, such as Toll-like receptors (TLRs), correlates with pro-tumoral inflammation and cancer progression, but the mechanism is still largely unknown. Deciphering the proinflammatory mediators in tumor microenvironment will contribute to the development of cancer therapeutics. By using immunohistochemistry in pancreatic ductal adenocarcinoma (PDAC) and multiple other cancer samples, here we found that cancer cell TLR3, a well-known cytoplasmic dsRNA sensor, translocated to the nucleus especially upon chemotherapy stress. Nuclear TLR3 increased the invasive and proliferative properties, and inhibited chemotherapy-induced apoptosis of cancer cells in vitro. Meanwhile, mice bearing cancer cells with nuclear TLR3 exhibited increased liver metastasis and shortened survival. Mechanistically, phosphokinase JAK1 was responsible for TLR3 phosphorylation at S155 to induce its nuclear translocation in cooperation with a nuclear transport factor importin α5. Chemotherapeutic stress induced the aberrant aggregation of dsRNA in the nucleus, which potentially contributed to nuclear TLR3 activation. Then nuclear TLR3 recruited protein arginine methyltransferase 5 (PRMT5) and bound to c-Myc to promote symmetrical dimethylation and multimerization of c-Myc, resulting in the activation of c-Myc downstream target genes and pro-tumoral signaling pathways. Accordingly, high levels of cancer cell nuclear TLR3 in clinical samples predicted patients’ worse prognosis with shorter disease-free survival, overall survival and poor response to neoadjuvant chemotherapy. Therefore, the identification of nuclear TLR3 provides new insight into non-classical functions of innate immune sensors in cancer, and JAK1/TLR3/PRMT5/c-Myc axis may sever as a new prognostic indicator and potential therapeutic target to overcome chemoresistance.

2025-06-30 | GSE299145 | GEO

Eutherian interferons

Project description:Eutherian interferons

| PRJEB36709 | ENA

Complete TLR3 deficiency

Project description:The objective of this study is to study the Toll-like receptor 3 (TLR3)-dependent gene expression in human fibroblast cells and peripheral blood mononuclear cells (PBMCs) Fibroblast cells and PBMCs from donors with autosomal recessive (AR) complete TLR3 deficiency and autosomal dominant (AD) partial TLR3 deficiency were collected for microarray analysis to measure the transcriptional responsiveness of TLR3 in fibroblast and PBMCs. A total of 3 healthy controls, 1 AD TLR3-deficient patient, 1 AR TLR3-deficient patient, 1 AR UNC-93B-deficient patient, 1 MyD88 deficient patien were used in this study. The fibroblast cells were cultured in DMEM medium supplemented with 10% fetal calf serum (FCS). The PBMCs were cultured in RPMI medium complemented with 10% FCS. Different kinetics (2 hours and 8 hours) of poly(I:C) (25ug/ml, purchased from Amersham) stimulations were performed, aiming to define TLR3-inducible genes in these human cells. A stimulation of IL-1β (20ng/ml, purchased from R&D system Inc.) was used as a positive activation control with same kinetics of stimulations. A total of one million cells per stimulation were used for fibroblasts, and around 1.5 million cells per stimulation for PBMCs.

2011-11-02 | E-GEOD-30951 | biostudies-arrayexpress

Assessment of the impact of the TLR3 L412F variant in terms of TLR3-sensitive transcript induction

Project description:we assessed the impact of TLR3 L412F at endogenous cellular levels upon double stranded RNA (dsRNA) stimulation, by performing RNA-sequencing in primary fibroblasts from individuals homozygous for the ancestral allele (n =2) or homozygous for TLR3 L412F (n = 4) upon extracellular Poly(I:C) stimulation that activates the TLR3 pathway. The average response of TLR3 L412F homozygotes was significantly decreased (mean Δ log2 fold-change = 0.93; Wilcoxon p <10-16) compared to that of cells with the ancestral allele, approaching that of TLR3-deficient cells, used as negative control.

2023-01-13 | GSE216304 | GEO

ImmGen Cytokines: Interferons

Project description:ImmGen Cytokines: Interferons

| PRJNA303161 | ENA

Therapeutic anti-glioma effect of the combined action of PCSK inhibitor with the anti-tumoral factors secreted by Poly (I:C) - stimulated macrophages

Project description:Macrophages plasticity is a key feature in cancer progression. Neoplastic cells can alter their immune functions and orient them into a pro-tumoral phenotype. In this context and based on our previous work, we developed a new therapeutic strategy to switch macrophages phenotype and reactivate their anti-tumoral functions. In this context, we previously showed a dual activity of a proprotein convertases inhibitor as anti-glioma drug and anti-tumoral macrophages’ reactivation drug. Proprotein convertases are proteases that cleave proteins into functional proteins. Several of their substrates are involved in tumorigenesis and immunosuppression. In this study, we decided to combine proprotein convertases inhibitor with Poly (I:C), a TLR3 ligand, to increase the anti-tumoral activity of macrophages. With mass spectrometry-based proteomics we could establish that a stimulation of macrophages with Poly (I:C) increased their secretion of pro-inflammatory cytokines and anti-tumoral factors. 3D invasion assay showed the efficacy of these anti-tumoral factors against mixed glioma cells and macrophages spheroids. Besides, immunofluorescence and proliferation assays showed an additive effect of the proprotein convertases inhibitor and the anti-tumoral factors secreted by Poly (I:C)-treated macrophages on both anti-glioma activity and macrophages anti-tumoral orientation leading to an innovative glioma therapy.

2021-09-23 | PXD020258 | Pride

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