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Deciphering how microbiota modulate anti-tumor immune responses in checkpoint therapy

Project description

Mechanisms of anti-tumour immune response regulations by the microbiota

The microbiota impacts anti-tumour immune responses and the efficacy of anticancer treatments. What microbiota-derived signals are involved in this phenomenon remains poorly understood. The aryl hydrocarbon receptor (AhR) is a transcription factor sensing products derived from diet and microbiota metabolism. Based on previous work, researchers of the EU-funded MIMIC project hypothesise that AhR could be involved in the modulation of anti-tumour responses by the microbiota via the regulation of immune cells. The project will address whether AhR ligands mediate the impact of the microbiota on anti-tumour responses in anti-checkpoint therapy and the mechanisms involved. The study involves the analysis of anti-tumour immune responses in mice with normal or altered microbiota, in combination with anti-checkpoint therapy and a diet supplemented for AhR ligands.

Objective

Microbiota has a major impact on anti-tumor immune responses and efficacy of anticancer treatments. These effects are thought to be mediated by modulation of tumor-infiltrating myeloid cells. These include immunosuppressive macrophages that differentiate from inflammatory monocytes recruited to the tumor. However, what microbiota-derived products are required for efficient anti-tumoral responses is still unclear. We have recently identified the Aryl Hydrocarbon Receptor (AhR) as a key suppressor of monocyte-to-macrophage differentiation. AhR is a ligand-activated transcription factor sensing metabolites derived mainly from dietary intake and microbiota metabolism. Based on our previous work, we hypothesize that AhR is involved in the modulation of anti-tumoral responses by the microbiota, via the regulation of immune cells differentiation or function. The objective of the project is to address whether AhR ligands mediate the impact of microbiota on anti-tumor responses in anti-checkpoint therapy and to determine the cellular mechanisms involved. To address it, we will analyse anti-tumor immune responses in groups of mice with normal or altered microbiota, treated or not with anticheckpoint therapy, fed with a control diet or supplemented for AhR ligands. We will combine two complimentary approaches, employing antibiotics to deplete the microbiota or using germfree mice. The efficacy of immunotherapies using checkpoint inhibitors is greatly reduced in patients who receive antibiotics. This is a major issue as antibiotics are commonly prescribed to prevent or treat infections in cancer patients, who may be vulnerable. This research project will provide critical novel insight into the complex interplay between microbiota and anti-tumor immune responses. Results from this project will be instrumental in designing novel strategies for improving anti-tumoral immunotherapies.

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MSCA-IF-EF-ST - Standard EF

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(opens in new window) H2020-MSCA-IF-2018

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INSTITUT CURIE
Net EU contribution

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€ 184 707,84
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RUE D ULM 26
75231 Paris
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Ile-de-France Ile-de-France Paris
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 184 707,84
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