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

Descripción del proyecto

Lo mecanismos de la microbiota que regulan la respuesta inmunitaria antitumoral

La microbiota afecta a las respuestas inmunitarias antitumorales y a la eficacia de los tratamientos antineoplásicos. Sin embargo, aún se desconoce la implicación de las señales derivadas de la microbiota en este fenómeno. El receptor de hidrocarburos de arilo (AhR, por sus siglas en inglés) es un factor de transcripción que detecta productos derivados de la dieta y del metabolismo de la microbiota. Basándose en trabajos previos, los investigadores del proyecto financiado con fondos europeos MIMIC plantean la hipótesis de que el AhR podría estar implicado en la modulación de las respuestas antitumorales de la microbiota a través de la regulación de las células inmunitarias. El proyecto estudiará si los ligandos del AhR median en el impacto de la microbiota en las respuestas antitumorales en la terapia contra los puntos de control y los mecanismos implicados. El estudio incluye el análisis de respuestas inmunitarias antitumorales en ratones con una microbiota normal o alterada en combinación con terapia contra los puntos de control y un suplemento alimentario para los ligandos del AhR.

Objetivo

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.