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

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

PROVIDER: PRJNA857660 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20077410_1.fastq.gz	Fastqsanger.gz
	SRR20077410_2.fastq.gz	Fastqsanger.gz
	SRR20077411_1.fastq.gz	Fastqsanger.gz
	SRR20077411_2.fastq.gz	Fastqsanger.gz
	SRR20077412_1.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 [scRNA-seq]

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

2022-07-22 | GSE207947 | GEO

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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Transcriptomic studies on ruxolitinib with or without checkpoint inhibitors as a cancer therapy

Project description:Unleashing anti-tumor T cell activity by checkpoint inhibition is effective in many cancer patients but clinical response rates remain limited. Myeloid derived suppressor cells erode antitumor lymphocyte numbers and function, and correlate with resistance to checkpoint inhibitors. By screening small molecule libraries, we identified JAK inhibitors’ ability to rescue T cell function. Despite its documented immune suppressive properties, the prototypical JAK inhibitor ruxolitinib enhanced the efficacy of immune checkpoint blockade in cancer. This effect correlated with loss of suppressive gene expression, and acquisition of immunostimulatory molecular markers and T cell stimulatory activity in myeloid cells. In preclinical models, ruxolitinib significantly improved the function and increased the total numbers of activated tumor-infiltrating NK and CD4 T cells compared to checkpoint blockade alone and the efficacy was conditional on granulocytic cells. In addition to myeloid reprogramming in the tumor, ruxolitinib blunts G-CSF signaling in the bone marrow to prevent expression of suppressive and chemotaxis genes in neutrophils.

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RIG-I activating immunostimulatory RNA boosts the efficacy of anticancer vaccines and synergizes with immune checkpoint blockade.

Project description:BackgroundAntibody-mediated targeting of regulatory T cell receptors such as CTLA-4 enhances antitumor immune responses against several cancer entities including malignant melanoma. Yet, therapeutic success in patients remains variable underscoring the need for novel combinatorial approaches.MethodsHere we established a vaccination strategy that combines engagement of the nucleic acid-sensing pattern recognition receptor RIG-I, antigen and CTLA-4 blockade. We used in vitro transcribed 5'-triphosphorylated RNA (3pRNA) to therapeutically target the RIG-I pathway. We performed in vitro functional analysis in bone-marrow derived dendritic cells and investigated RIG-I-enhanced vaccines in different murine melanoma models.FindingsWe found that protein vaccination together with RIG-I ligation via 3pRNA strongly synergizes with CTLA-4 blockade to induce expansion and activation of antigen-specific CD8+ T cells that translates into potent antitumor immunity. RIG-I-induced cross-priming of cytotoxic T cells as well as antitumor immunity were dependent on the host adapter protein MAVS and type I interferon (IFN-I) signaling and were mediated by dendritic cells.InterpretationOverall, our data demonstrate the potency of a novel combinatorial vaccination strategy combining RIG-I-driven immunization with CTLA-4 blockade to prevent and treat experimental melanoma. FUND: German Research Foundation (SFB 1335, SFB 1371), EMBO, Else Kröner-Fresenius-Foundation, German Cancer Aid, European Hematology Association, DKMS Foundation for Giving Life, Dres. Carl Maximilian and Carl Manfred Bayer-Foundation.

| S-EPMC6444128 | biostudies-literature

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