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

Lauren Giuffrida, Kevin Sek, Melissa A. Henderson, Junyun Lai, Amanda X. Y. Chen, Deborah Meyran, Kirsten L. Todd, Emma V. Petley, Sherly Mardiana, Christina Mølck, Gregory D. Stewart, Benjamin J. Solomon, Ian A. Parish, Paul J. Neeson, Simon J. Harrison, Lev M. Kats, Imran G. House (), Phillip K. Darcy () and Paul A. Beavis ()
Additional contact information
Lauren Giuffrida: Peter MacCallum Cancer Centre
Kevin Sek: Peter MacCallum Cancer Centre
Melissa A. Henderson: Peter MacCallum Cancer Centre
Junyun Lai: Peter MacCallum Cancer Centre
Amanda X. Y. Chen: Peter MacCallum Cancer Centre
Deborah Meyran: Peter MacCallum Cancer Centre
Kirsten L. Todd: Peter MacCallum Cancer Centre
Emma V. Petley: Peter MacCallum Cancer Centre
Sherly Mardiana: Peter MacCallum Cancer Centre
Christina Mølck: University of Melbourne
Gregory D. Stewart: Monash University
Benjamin J. Solomon: The University of Melbourne
Ian A. Parish: Peter MacCallum Cancer Centre
Paul J. Neeson: Peter MacCallum Cancer Centre
Simon J. Harrison: The University of Melbourne
Lev M. 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, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23331-5

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