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- Title
CRISPR/Cas9 mediated deletion of the adenosine A2A receptor enhances CAR T cell efficacy.
- Authors
Giuffrida, Lauren; Sek, Kevin; Henderson, Melissa A.; Lai, Junyun; Chen, Amanda X. Y.; Meyran, Deborah; Todd, Kirsten L.; Petley, Emma V.; Mardiana, Sherly; Mølck, Christina; Stewart, Gregory D.; Solomon, Benjamin J.; Parish, Ian A.; Neeson, Paul J.; Harrison, Simon J.; Kats, Lev M.; House, Imran G.; Darcy, Phillip K.; Beavis, Paul A.
- Abstract
Adenosine is an immunosuppressive factor that limits anti-tumor immunity through the suppression of multiple immune subsets including T cells via activation of the adenosine A2A receptor (A2AR). Using both murine and human chimeric antigen receptor (CAR) T cells, here we show that targeting A2AR with a clinically relevant CRISPR/Cas9 strategy significantly enhances their in vivo efficacy, leading to improved survival of mice. Effects evoked by CRISPR/Cas9 mediated gene deletion of A2AR are superior to shRNA mediated knockdown or pharmacological blockade of A2AR. Mechanistically, human A2AR-edited CAR T cells are significantly resistant to adenosine-mediated transcriptional changes, resulting in enhanced production of cytokines including IFNγ and TNF, and increased expression of JAK-STAT signaling pathway associated genes. A2AR deficient CAR T cells are well tolerated and do not induce overt pathologies in mice, supporting the use of CRISPR/Cas9 to target A2AR for the improvement of CAR T cell function in the clinic. Activation of the adenosine receptor A2AR is associated with suppression of T cell function in the tumor microenvironment. To overcome immunosuppression, here the authors show that CRISPR/Cas9 mediated deletion of A2AR enhances CAR T cell effector functions without altering memory or persistence properties, improving CAR-T mediated tumor control in pre-clinical models.
- Subjects
T cells; CRISPRS; JAK-STAT pathway; AUTOMOBILES; GENOME editing; CHIMERIC antigen receptors; ADENOSINES; TUMOR necrosis factors
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-23331-5