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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.
Nature communications, 05/2021, Letnik: 12, Številka: 1Journal Article
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 A 2A receptor (A 2A R). Using both murine and human chimeric antigen receptor (CAR) T cells, here we show that targeting A 2A R 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 A 2A R are superior to shRNA mediated knockdown or pharmacological blockade of A 2A R. Mechanistically, human A 2A R-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. A 2A R deficient CAR T cells are well tolerated and do not induce overt pathologies in mice, supporting the use of CRISPR/Cas9 to target A 2A R for the improvement of CAR T cell function in the clinic.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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