Tumor site-directed A1R expression enhances CAR T cell function and improves efficacy against solid tumors
- Author(s)
- Sek, K; Chen, AXY; Cole, T; Armitage, JD; Tong, J; Yap, KM; Munoz, I; Dunbar, PA; Wu, S; van Elsas, MJ; Hidajat, O; Scheffler, C; Giuffrida, L; Henderson, MA; Meyran, D; Souza-Fonseca-Guimaraes, F; Nguyen, D; Huang, YK; de Menezes, MN; Derrick, EB; Chan, CW; Todd, KL; Chan, JD; Li, J; Lai, J; Petley, EV; Mardiana, S; Bosco, A; Waithman, J; Parish, IA; Molck, C; Stewart, GD; Kats, L; House, IG; Darcy, PK; Beavis, PA;
- Journal Title
- Nature Communications
- Publication Type
- Research article
- 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 A(2A) receptor. To overcome this, Chimeric Antigen Receptor T cells are engineered to express A(1) receptor, a receptor that signals inversely to A(2A) receptor. Using murine and human Chimeric Antigen Receptor T cells, constitutive A(1) 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 A(1) 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 A(2A) 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.
- Keywords
- Animals; Humans; Mice; *Receptors, Chimeric Antigen/genetics/metabolism/immunology; *Neoplasms/therapy/immunology/genetics; *Immunotherapy, Adoptive/methods; *T-Lymphocytes/immunology/metabolism; CRISPR-Cas Systems; Tumor Microenvironment/immunology; Cell Line, Tumor; Female; Receptor, Adenosine A2A/genetics/metabolism; Mice, Inbred C57BL
- Department(s)
- Laboratory Research
- Publisher's Version
- https://doi.org/10.1038/s41467-025-59021-9
- Open Access at Publisher's Site
https://doi.org/10.1038/s41467-025-59021-9- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-08-08 07:40:19
Last Modified: 2025-08-08 07:42:02