Tumor site-directed A1R expression enhances CAR T cell function and improves efficacy against solid tumors
Brief intro:
- Author: 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
- Journal: Nature Communications
- Doi: https://www.doi.org/10.1038/s41467-025-59021-9
- Publication Date: 2025/7/3
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.
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