Details

Autor(en) / Beteiligte

• 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.

Titel

CRISPR/Cas9 mediated deletion of the adenosine A2A receptor enhances CAR T cell efficacy

Ist Teil von

• Nature communications, 2021-05, Vol.12 (1), p.3236-3236, Article 3236

Ort / Verlag

London: Nature Publishing Group

Erscheinungsjahr

2021

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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.