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Intralesional TLR4 agonist treatment strengthens the organ defense against colonizing cancer cells in the brain

ABSTRACT: Intralesional TLR4 agonist treatment strengthens the organ defense against colonizing cancer cells in the brain

PROVIDER: PRJNA805239 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17976553.fastq.gz	Fastqsanger.gz
	SRR17976556.fastq.gz	Fastqsanger.gz
	SRR17976558.fastq.gz	Fastqsanger.gz
	SRR17976559.fastq.gz	Fastqsanger.gz
	SRR17976560.fastq.gz	Fastqsanger.gz

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Intralesional TLR4 agonist treatment strengthens the organ defense against colonizing cancer cells in the brain

Project description:Brain metastasis in breast cancer remains difficult to treat and its incidence is increasing. Therefore, the development of new therapies is of utmost clinical relevance. Recently, toll-like receptor (TLR) 4 was correlated with IL6 expression and poor prognosis in 1 215 breast cancer primaries. In contrast, we demonstrated that TLR4 stimulation reduces microglia-assisted breast cancer cell invasion. However, the expression, prognostic value, or therapeutic potential of TLR signaling in breast cancer brain metastasis have not been investigated. We thus tested the prognostic value of various TLRs in two brain-metastasis gene sets. Furthermore, we investigated different TLR agonists, as well as MyD88 and TRIF-deficient microenvironments in organotypic brain-slice ex vivo co- cultures and in vivo colonization experiments. These experiments underline the ambiguous roles of TLR4, its adapter MyD88, and the target nitric oxide (NO) during brain colonization. Moreover, analysis of the gene expression datasets of breast cancer brain metastasis patients revealed associations of TLR1 and IL6 with poor overall survival. Finally, our finding that a single LPS application at the onset of colonization shapes the later microglia/macrophage reaction at the macro-metastasis brain-parenchyma interface (MMPI) and reduces metastatic infiltration into the brain parenchyma may prove useful in immunotherapeutic considerations.

2022-12-04 | GSE196519 | GEO

Intralesional TLR4 agonist treatment strengthens the organ defense against colonizing cancer cells in the brain.

Project description:Brain metastasis in breast cancer remains difficult to treat and its incidence is increasing. Therefore, the development of new therapies is of utmost clinical relevance. Recently, toll-like receptor (TLR) 4 was correlated with IL6 expression and poor prognosis in 1 215 breast cancer primaries. In contrast, we demonstrated that TLR4 stimulation reduces microglia-assisted breast cancer cell invasion. However, the expression, prognostic value, or therapeutic potential of TLR signaling in breast cancer brain metastasis have not been investigated. We thus tested the prognostic value of various TLRs in two brain-metastasis gene sets. Furthermore, we investigated different TLR agonists, as well as MyD88 and TRIF-deficient microenvironments in organotypic brain-slice ex vivo co-cultures and in vivo colonization experiments. These experiments underline the ambiguous roles of TLR4, its adapter MyD88, and the target nitric oxide (NO) during brain colonization. Moreover, analysis of the gene expression datasets of breast cancer brain metastasis patients revealed associations of TLR1 and IL6 with poor overall survival. Finally, our finding that a single LPS application at the onset of colonization shapes the later microglia/macrophage reaction at the macro-metastasis brain-parenchyma interface (MMPI) and reduces metastatic infiltration into the brain parenchyma may prove useful in immunotherapeutic considerations.

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Study of Intratumoral Ipilimumab and TLR4 Agonist GLA-SE in Combination With Systemic Nivolumab and Chemotherapy

Project description:To determine the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D) and the toxicity profile (NCI CTCAE v5.0 and immune related adverse events) of i.t. administration of anti-CTLA4 antibody (ipilimumab) and TLR4 agonist (synthetic glucopyranosyl lipid A formulated in a stable emulsion [GLA-SE]) in colorectal LM (CRLM) in combination with intravenous (i.v.) administration of anti-PD-1 antibody (nivolumab) and chemotherapy (FOLFOX regimen).

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Intratumoral injection of TLR4 agonist GLA in A20 tumor model

Project description:The goal of this study was to investigate the effect of intratumoral injection of GLA-SE, a TLR4 agonist in stable emulsion (SE), in Balb/c mice with established A20 lymphoma.

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Intratumoral injection of TLR4 agonist GLA in A20 tumor model

Project description:Intratumoral injection of TLR4 agonist GLA in A20 tumor model

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Immunoresponsive Gene 1 Facilitates TLR4-agonist-Induced Augmentation of Innate Antimicrobial Immunity

Project description:Immunoresponsive Gene 1 Facilitates TLR4-agonist-Induced Augmentation of Innate Antimicrobial Immunity

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Gut microbiota-derived GlcNAc-MurNAc is a TLR4 agonist that protects the host gut

Project description:Gut microbiota-derived peptidoglycan fragments (PGNs) are key signaling molecules that regulate multiple aspects of the host’s health. Yet the exact structures of natural PGNs in hosts have not been fully elucidated. Herein, we developed an LC-HRMS/MS analytical platform for global quantification and profiling of natural PGN subtypes in host gut and sera, unexpectedly revealing the abundance of PGN-derived saccharide moieties that do not resemble canonical ligands of mammalian NOD1/2 receptors. Focusing on the disaccharide GlcNAc-MurNAc (GM), which does not activate NOD1/2 yet still exhibits immunostimulatory effects in host immune cells, we established GM as a mild TLR4 agonist, illustrating an alternate PGN sensing mechanism other than NOD signaling. Importantly, the administration of GM mitigates colonic inflammation in the DSS-induced colitis model in mice via a TLR4-dependent manner, highlighting the in vivo significance of gut microbiota-derived PGN saccharides in maintaining host intestinal homeostasis.

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Molecular and cellular response profiles induced by the TLR4 agonist-based adjuvant Glucopyranosyl Lipid A

Project description:Toll-like receptor (TLR)4 agonists are known potent immunostimulatory compounds. These compounds can be formulated as part of novel adjuvants to enhance vaccine medicated immune responses. However, the contribution of the formulation to the innate in vivo activity of TLR4 agonist compounds is not well understood. Molecular expression profiles and cellular responses in a mouse model were used to compare for GLA-SE, GLA, Alum, SE, PBS. This study was to evaluate the mechanism of actions of different adjuvants and to identify potential biomarkers for clinical evaluation.

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Molecular and cellular response profiles induced by the TLR4 agonist-based adjuvant Glucopyranosyl Lipid A

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Gut microbiota-derived GlcNAc-MurNAc is a TLR4 agonist that protects the host gut

Project description:Gut microbiota-derived GlcNAc-MurNAc is a TLR4 agonist that protects the host gut

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