Tumor site-directed A1R expression enhances CAR T cell function and improves efficacy against solid tumors

Tumor site-directed A1R expression enhances CAR T cell function and improves efficacy against solid tumors

Abstract The efficacy of Chimeric Antigen Receptor T cells against solid tumors is limited by immunosuppressive factors in the tumor microenvironment including adenosine, which suppresses Chimeric Antigen Receptor T cells through activation of the A2A receptor. To overcome this, Chimeric Antigen Rec...

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Main Authors: Kevin Sek, Amanda X. Y. Chen, Thomas Cole, Jesse D. Armitage, Junming Tong, Kah Min Yap, Isabelle Munoz, Phoebe A. Dunbar, Shiyi Wu, Marit J. van Elsas, Olivia Hidajat, Christina Scheffler, Lauren Giuffrida, Melissa A. Henderson, Deborah Meyran, Fernando Souza-Fonseca-Guimaraes, Dat Nguyen, Yu-Kuan Huang, Maria N. de Menezes, Emily B. Derrick, Cheok Weng Chan, Kirsten L. Todd, Jack D. Chan, Jasmine Li, Junyun Lai, Emma V. Petley, Sherly Mardiana, Anthony Bosco, Jason Waithman, Ian A. Parish, Christina Mølck, Gregory D. Stewart, Lev Kats, Imran G. House, Phillip K. Darcy, Paul A. Beavis
Format: Article
Language:English
Published: Nature Portfolio 2025-07-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-59021-9
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Summary:Abstract The efficacy of Chimeric Antigen Receptor T cells against solid tumors is limited by immunosuppressive factors in the tumor microenvironment including adenosine, which suppresses Chimeric Antigen Receptor T cells through activation of the A2A receptor. To overcome this, Chimeric Antigen Receptor T cells are engineered to express A1 receptor, a receptor that signals inversely to A2A receptor. Using murine and human Chimeric Antigen Receptor T cells, constitutive A1 receptor overexpression significantly enhances Chimeric Antigen Receptor T cell effector function albeit at the expense of Chimeric Antigen Receptor T cell persistence. Through a CRISPR/Cas9 homology directed repair “knock-in” approach we demonstrate that Chimeric Antigen Receptor T cells engineered to express A1 receptor in a tumor-localized manner, enhances anti-tumor therapeutic efficacy. This is dependent on the transcription factor IRF8 and is transcriptionally unique when compared to A2A receptor deletion. This data provides a novel approach for enhancing Chimeric Antigen Receptor T cell efficacy in solid tumors and provides proof of principle for site-directed expression of factors that promote effector T cell differentiation.
ISSN:2041-1723

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