MIMIC · Deciphering how microbiota modulate anti-tumor immune responses in checkpoint therapy
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-04-01 → 2022-03-31
- EU contribution
- €184,708
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Deciphering how microbiota modulate anti-tumor immune responses in checkpoint therapy
Responses to immunotherapies against cancers can be affected by multiple factors, including environmental signals. In particular, nutrition could represent an important player, as it can modulate the immune system through small molecules produced during digestion or by the intestinal flora. There is scientific evidence that dietary interventions could provide clinical benefits to patients being treated with checkpoint blockade therapy such as anti-PD1. In addition, several studies have shown a link between the intestinal microbiota and the efficacy of anti-tumor therapies, including checkpoint blockade. However, our knowledge of the direct effects of dietary nutrients on anti-tumor immune responses is still limited. In our laboratory, we are interested in a molecule called Aryl Hydrocarbon Receptor (AhR) recognizing products produced by the digestion of certain vegetables (such as brocoli and cauliflower) and by a portion of the intestinal microbiota (such as Lactobacilli bacteria). Based on our previous work, we hypothesized that nutrients recognized by AhR play a role in immune responses against tumors. The specific aims of this project were to determine which immune cells are modulated by these nutrients and how their properties are affected during anti-PD1 treatment in mouse models. We found that the presence of the AhR-activating nutrient in the diet, but not from the intestinal microbiota, was essential for the efficacy of checkpoint blockade therapy with anti-PD1.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- INSTITUT CURIE · ParisCoordinatorFrance
Links
Data: CORDIS, © European Union