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

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

Abstract 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 fun...

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Main Authors: Valentine De Castro, Oumaïma Abdellaoui, Barbara Dehecq, Babacar Ndao, Patricia Mercier-Letondal, Alexandra Dauvé, Francine Garnache-Ottou, Olivier Adotévi, Romain Loyon, Yann Godet
Format: Article
Language:English
Published: Springer 2025-05-01
Series:Cancer Immunology, Immunotherapy
Subjects:
AHR
T cell dysfunction
CRISPR-Cas9
CAR-T cell therapy
Online Access:https://doi.org/10.1007/s00262-025-04065-5
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Summary:Abstract 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.
ISSN:1432-0851

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