Characterization of the aryl hydrocarbon receptor as a potential candidate to improve cancer T cell therapies.

Fiche publication

Date publication

mai 2025

Journal

Cancer immunology, immunotherapy : CII

Auteurs

Membres identifiés du Cancéropôle Est :
Pr ADOTEVI Olivier , Pr GARNACHE-OTTOU Francine , Dr GODET Yann , Dr LOYON Romain

Tous les auteurs :
De Castro V, Abdellaoui O, Dehecq B, Ndao B, Mercier-Letondal P, Dauvé A, Garnache-Ottou F, Adotévi O, Loyon R, Godet Y

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/40358739

Résumé

The efficacy of T-cell-based cancer therapies can be limited by the tumor microenvironment which can lead to T cell dysfunction. Multiple studies, particularly in murine models, have demonstrated the capacity of the aryl hydrocarbon receptor (AHR) to negatively regulate antitumor T cell functions. AHR is a cytoplasmic receptor and transcription factor that was originally identified as a xenobiotic sensor, but has since been shown to play a significant role in the gene regulation of various immune cells, including T cells. Given the insights from murine studies, AHR emerges as a promising candidate to invalidate for optimizing T cell-based cancer therapies. However, the controversial role of AHR in human T cells underscores the need for a more comprehensive characterization of AHR expressing T cells. This study aims to investigate the regulatory mechanisms of AHR in human T cell biology to better understand its impact on reducing antitumor immune responses. Here, we knocked-out AHR in human T cells using CRISPR-Cas9 technology to characterize AHR's function in an in vitro chronic stimulation model. Engineered T cells exhibited enhanced effector- and memory-like profiles and expressed reduced amount of CD39 and TIGIT. AHR knockout enhanced human CAR-T cells' functionality and persistence upon tumor chronic stimulation. Collectively, these results highlight the role of AHR in human CAR-T cells efficiency.