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A microbiome-produced metabolite drives immunostimulatory macrophages and boosts response to immune checkpoint inhibitors in pancreatic cancer [scRNA-seq]

ABSTRACT: A microbiome-produced metabolite drives immunostimulatory macrophages and boosts response to immune checkpoint inhibitors in pancreatic cancer [scRNA-seq]

PROVIDER: PRJNA857729 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20081785.fastq.gz	Fastqsanger.gz
	SRR20081786.fastq.gz	Fastqsanger.gz

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A microbiome-produced metabolite drives immunostimulatory macrophages and boosts response to immune checkpoint inhibitors in pancreatic cancer

Project description:A microbiome-produced metabolite drives immunostimulatory macrophages and boosts response to immune checkpoint inhibitors in pancreatic cancer

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A microbiome-produced metabolite drives immunostimulatory macrophages and boosts response to immune checkpoint inhibitors in pancreatic cancer [scRNA-seq]

Project description:The composition of the gut microbiome controls innate and adaptive immunity and has emerged as a key regulator of tumor growth and the success of immune checkpoint blockade (ICB) therapy. However, the underlying mechanisms remain unclear. Pancreatic ductal adenocarcinoma (PDAC) tends to be refractory to therapy, including ICB. We found that the gut microbe-derived metabolite trimethylamine N-oxide (TMAO) enhances anti-tumor immunity to PDAC. Delivery of TMAO given intraperitoneally or via dietary choline supplement to PDAC-bearing mice reduces tumor growth and is associated with an immunostimulatory tumor-associated macrophage (TAM) phenotype and activated effector T cell response in the tumor microenvironment. Mechanistically, TMAO signals through potentiating type-I interferon (IFN) pathway and confers anti-tumor effects in a type-I IFN dependent manner. Notably, delivering TMAO-primed macrophages alone produced similar anti-tumor effects. Combining TMAO with ICB (anti-PD1 and/or anti-Tim3) significantly reduced tumor burden and improved survival beyond TMAO or ICB alone. Finally, the levels of trimethylamine (TMA)-producing bacteria and of CutC gene expression associate with improved survivorship and response to anti-PD1 in cancer patients. Together, our study identifies the gut microbial metabolite TMAO as an important driver of anti-tumor immunity and lays the groundwork for new therapeutic strategies.

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A microbiome-produced metabolite drives immunostimulatory macrophages and boosts response to immune checkpoint inhibitors in pancreatic cancer [RNA-seq]

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A microbiome-produced metabolite drives immunostimulatory macrophages and boosts response to immune checkpoint inhibitors in pancreatic cancer [RNA-seq]

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A microbiome-produced metabolite drives immunostimulatory macrophages and boosts response to immune checkpoint inhibitors in pancreatic cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

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Faecalibaterium prausnitzii strain EXL01 boosts efficacy of Immune Checkpoint Inhibitors

Project description:Faecalibaterium prausnitzii strain EXL01 boosts efficacy of Immune Checkpoint Inhibitors

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Faecalibaterium prausnitzii strain EXL01 boosts efficacy of Immune Checkpoint Inhibitors

Project description:Gut microbiota impacts responses to immune checkpoint inhibitors (ICI). High level of Faecalibacterium prausnitzii has been associated with a positive response to ICI in multiple cancer types. Here, we show in two independent cohorts of patients with non-small cell lung cancer and advanced melanoma that high level of F. prausnitzii at baseline is positively associated with a better clinical response to ICI. In a mouse preclinical model, we show that the F. prausnitzii strain EXL01, already in clinical development for Inflammatory Bowel Disease, restores the anti-tumor response to ICI in the context of antibiotic-induced microbiota perturbation at clinical and tumor transcriptomics level. In vitro, EXL01 strain enhances T cell activation in the presence of ICI. Interestingly, oral administration of EXL01 strain is not associated with a change in fecal microbiota diversity or composition suggesting a direct effect on immune cells in the small intestine.

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| S-EPMC6444128 | biostudies-literature

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