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

Informations projet

MIMIC

N° de convention de subvention: 842535

DOI

10.3030/842535

Projet clôturé

Date de signature de la CE 24 Avril 2019

Date de début 1 Avril 2020

Date de fin 31 Mars 2022

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 184 707,84

Contribution de l’UE

€ 184 707,84

Coordonné par

INSTITUT CURIE
France

Periodic Reporting for period 1 - MIMIC (Deciphering how microbiota modulate anti-tumor immune responses in checkpoint therapy)

Période du rapport: 2020-04-01 au 2022-03-31

Résumé du contexte et des objectifs généraux du projet

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.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

To study the impact of dietary AhR ligands on immune responses in vivo, we used a mouse model. Tumors were induced in mice by injecting fibrosarcoma cells. To address the impact of dietary activators of AhR, we compared groups of mice fed with a diet containing or not a purified nutrient that is naturally found in brocoli. To address the impact of microbiota-derived activators of AhR, we compared groups of mice treated or not with antibiotics that specifically target the group of bacteria producing these molecules.
We found that the presence of the AhR-activating nutrient in the diet was essential for the efficacy of checkpoint blockade therapy with anti-PD1. By contrast, the elimination of AhR-producing bacteria with antibiotics did not impact the efficacy of treatment. These results indicated the source of the AhR-activating molecules plays an important role in this phenomenon.
Using a series of advanced techniques for analyzing the immune cells that populate the tumors, we identified which immune cells are directly impacted by the AhR-activating nutrient. The final stage of the project will be to analyze how exactly the function of these cells is changed by the absence or presence of this nutrient in the diet.
These results identify an important role fo AhR-activating molecules produced from diet, but not from intestinal microbiota, in the efficacy of anti-checkpoint therapy. These results will be submitted for publication in a high-impact peer-reviewed journal, and will be presented in international conferences (both in the fields of immunology and cancer immunotherapies).

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

Results from this project will be essential in building an integrated view of the interactions between nutrition, cancer and immune responses. Our findings will allow a better understanding of the impact of food products on anti-tumor immune responses. It will provide a rationale for optimizing diet monitoring of cancer patients being treated with checkpoint blockade therapy, and a proof-of-concept for dietary interventions to ameliorate the response of patients treated with checkpoint blockade therapy. Beyond cancer, PD1 blockade has shown therapeutic potential in models of chronic infections (such as hepatitis B, HIV and blood-stage malaria) and sepsis. Our work will have important implications for optimizing such immunotherapies employing PD1 blockade.

The role of AhR in cancer immuno-surveillance remains unclear. Our results will provide new knowledge on the complex role of AhR in tumor immunity, as well as critical information for future studies evaluating the value of AhR inhibition for anti-tumoral treatments. In addition, because AhR can also bind xenobiotics (which induce aberrant AhR signalling), our results should contribute to future work addressing the impact of AhR-binding pollutants on the efficacy of checkpoint blockade therapy.

In conclusion, we anticipate that this project will have significant immediate value for cancer patients for dietary interventions to improve their treatment, as well as longer-term implications for optimizing therapeutic strategies using checkpoint blockade or AhR inhibitors.

Graphical summary