Summary of Study ST002216

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001416. The data can be accessed directly via it's Project DOI: 10.21228/M8PM6K This work is supported by NIH grant, U2C- DK119886.

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This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST002216
Study TitleNon-targeted metabolomics screen comparing metabolite profiles of serum from PDAC-bearing mice that received metronidazole using high-resolution, high-performance LC-MS/MS analysis.
Study SummaryThe 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 TMAOprimed 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 correlate 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.
Institute
Wistar Institute
Last NameShinde
First NameRahul
Address3601 Spruce St, Philadelphia, PA 19104
Emailrshinde@wistar.org
Phone215-898-3717
Submit Date2022-07-11
Raw Data AvailableYes
Raw Data File Type(s)raw(Thermo)
Analysis Type DetailLC-MS
Release Date2022-07-22
Release Version1
Rahul Shinde Rahul Shinde
https://dx.doi.org/10.21228/M8PM6K
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Project:

Project ID:PR001416
Project DOI:doi: 10.21228/M8PM6K
Project Title:The microbiome-derived metabolite TMAO drives immune activation and boosts response to immune checkpoint blockade in pancreatic cancer
Project Summary: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 TMAOprimed 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 correlate 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.
Institute:The Wistar Institute
Last Name:Shinde
First Name:Rahul
Address:3601 Spruce St, Philadelphia, PA 19104
Email:rshinde@wistar.org
Phone:215-898-3717

Subject:

Subject ID:SU002302
Subject Type:Mammal
Subject Species:Mus musculus
Taxonomy ID:10090
Species Group:Mammals

Factors:

Subject type: Mammal; Subject species: Mus musculus (Factor headings shown in green)

mb_sample_id local_sample_id Treatment
SA211899Control PDAC 4Control
SA211900Control PDAC 6Control
SA211901Control PDAC 8Control
SA211902Control PDAC 3Control
SA211903Control PDAC 7Control
SA211904Control PDAC 5Control
SA211905Control PDAC 2Control
SA211906Control PDAC 1Control
SA211907Metronidazole PDAC 1Metronidazole
SA211908Metronidazole PDAC 2Metronidazole
SA211909Metronidazole PDAC 5Metronidazole
SA211910Metronidazole PDAC 4Metronidazole
SA211911Metronidazole PDAC 3Metronidazole
SA211912QC-3n/a
SA211913QC-4n/a
SA211914QC-2n/a
SA211915QC-6n/a
SA211916QC-5n/a
Showing results 1 to 18 of 18

Collection:

Collection ID:CO002295
Collection Summary:Three weeks after treatment, mice were euthanized for the assessment of serum for non-targeted metabolomics screen by LC-MS/MS analysis.
Sample Type:Blood (serum)

Treatment:

Treatment ID:TR002314
Treatment Summary:C57BL6/J (B6) mice received orthotopic tumor implant of 1.5 X 10^5 PDAC cells into the pancreas and metronidazole antibiotic (Cayman Chemical Company, 900249) treatment in drinking water at 1mg/ml.

Sample Preparation:

Sampleprep ID:SP002308
Sampleprep Summary:Briefly, polar metabolites were extracted from serum samples with 10 times volume of ice-cold 80% methanol. Deproteinated supernatants were stored at -80 °C prior to analysis. A quality control (QC) sample was generated by pooling equal volumes of all samples immediately before LC-MS analysis.

Chromatography:

Chromatography ID:CH002680
Chromatography Summary:Hydrophilic interaction liquid chromatography (HILIC) was performed at 0.2 ml/min on a ZIC-pHILIC column (2.1 mm × 150 mm, EMD Millipore) at 45 °C. Solvent A was 20 mM ammonium carbonate, 0.1% ammonium hydroxide, pH 9.2, and solvent B was acetonitrile. The gradient was 85% B for 2 min, 85% B to 20% B over 15 min, 20% B to 85% B over 0.1 min, and 85% B for 8.9 min. The autosampler was held at 4 °C. For each analysis, 4 µl of sample was injected.
Instrument Name:Thermo Vanquish
Column Name:SeQuant ZIC-HILIC (150 x 2.1mm,5um)
Flow Gradient: 85% B for 2 min, 85% B to 20% B over 15 min, 20% B to 85% B over 0.1 min, and 85% B for 8.9 min.
Solvent A:100% water; 20 mM ammonium carbonate; 0.1% ammonium hydroxide, pH 9.5
Solvent B:100% acetonitrile
Chromatography Type:HILIC

Analysis:

Analysis ID:AN003625
Analysis Type:MS
Chromatography ID:CH002680
Num Factors:3
Num Metabolites:207
Rt Units:Minutes
Units:Normalized Peak Area
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