Ffar2 modulates dendritic cell-derived IL-27 and CD8+ T cell exhaustion in colorectal cancer
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ABSTRACT:
PROVIDER: PRJNA597993 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10799710_1.fastq.gz | Fastqsanger.gz | |||
| SRR10799710_2.fastq.gz | Fastqsanger.gz | |||
| SRR10799711_1.fastq.gz | Fastqsanger.gz | |||
| SRR10799711_2.fastq.gz | Fastqsanger.gz | |||
| SRR10799712_1.fastq.gz | Fastqsanger.gz |
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Project description:Background and aims: Gut microbial metabolites and their host signaling pathways hold therapeutic potential for colorectal cancer (CRC). One example is short-chain fatty acids (SCFA), which are microbial metabolites generated from dietary fiber. This study aims to determine the pathogenesis of CRC from the host-microbiota perspective and the contributions of Ffar2, a SCFA receptor, to CRC. Methods: We have employed Apc-based models of CRC in conjunction with Ffar2 knock-out (ko) mice, Ffar2 conditional ko mice, and Ffar2 chemical agonism to reveal how a microbial metabolite receptor influences tumorigenesis in the colon. Utilizing human CRC datasets from The Cancer Genome Atlas aided our discovery of the links between Ffar2 function in dendritic cells and tumoral T cell dysfunction. Herein, we also used preclinical CRC models to test IL-27p28 neutralization or Ffar2 agonism as proof of concept for CRC prevention and treatment. Results: We have identified a mechanism by which Ffar2 deficiency potentiates tumorigenesis by affecting gut barrier integrity that increases tumor bacterial load and then altering IL-27+ dendritic cell populations and tumor CD8+ T cell phenotype and function. These events create a tumor immune milieu notable for dying and over-activated DCs and exhausted CD8+ T cells, which enables tumor growth. Proof-of-concept experiments in mice employing IL-27p28 neutralization or Ffar2 agonism reduced tumor burden. Conclusions: Our data support that loss of Ffar2 signaling potentiates tumorigenesis via a “two-hit” model, first by gut barrier breach and then by immune cell dysfunction. Our work supports that altering Ffar2 signaling or neutralizing IL-27 represent potential immunotherapy CRC treatment strategies.
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Project description:Ffar2 modulates dendritic cell-derived IL-27 and CD8+ T cell exhaustion in colorectal cancer
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