Tumor site-directed A1R expression enhances CAR T cell function and improves efficacy against solid tumors
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 () and
Paul A. Beavis ()
Additional contact information
Kevin Sek: Peter MacCallum Cancer Centre
Amanda X. Y. Chen: Peter MacCallum Cancer Centre
Thomas Cole: Peter MacCallum Cancer Centre
Jesse D. Armitage: University of Western Australia
Junming Tong: Peter MacCallum Cancer Centre
Kah Min Yap: Peter MacCallum Cancer Centre
Isabelle Munoz: Peter MacCallum Cancer Centre
Phoebe A. Dunbar: Peter MacCallum Cancer Centre
Shiyi Wu: Peter MacCallum Cancer Centre
Marit J. van Elsas: Peter MacCallum Cancer Centre
Olivia Hidajat: Peter MacCallum Cancer Centre
Christina Scheffler: Peter MacCallum Cancer Centre
Lauren Giuffrida: Peter MacCallum Cancer Centre
Melissa A. Henderson: Peter MacCallum Cancer Centre
Deborah Meyran: Peter MacCallum Cancer Centre
Fernando Souza-Fonseca-Guimaraes: The University of Queensland
Dat Nguyen: Peter MacCallum Cancer Centre
Yu-Kuan Huang: Peter MacCallum Cancer Centre
Maria N. de Menezes: Peter MacCallum Cancer Centre
Emily B. Derrick: Peter MacCallum Cancer Centre
Cheok Weng Chan: Peter MacCallum Cancer Centre
Kirsten L. Todd: Peter MacCallum Cancer Centre
Jack D. Chan: Peter MacCallum Cancer Centre
Jasmine Li: Peter MacCallum Cancer Centre
Junyun Lai: Peter MacCallum Cancer Centre
Emma V. Petley: Peter MacCallum Cancer Centre
Sherly Mardiana: Peter MacCallum Cancer Centre
Anthony Bosco: The University of Arizona
Jason Waithman: University of Western Australia
Ian A. Parish: Peter MacCallum Cancer Centre
Christina Mølck: The University of Melbourne
Gregory D. Stewart: Monash University
Lev Kats: The University of Melbourne
Imran G. House: Peter MacCallum Cancer Centre
Phillip K. Darcy: Peter MacCallum Cancer Centre
Paul A. Beavis: Peter MacCallum Cancer Centre
Nature Communications, 2025, vol. 16, issue 1, 1-17
Abstract:
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.
Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59021-9
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DOI: 10.1038/s41467-025-59021-9
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