Journal article
CRISPR/Cas9 mediated deletion of the adenosine A2A receptor enhances CAR T cell efficacy
L Giuffrida, K Sek, MA Henderson, J Lai, AXY Chen, D Meyran, KL Todd, EV Petley, S Mardiana, C Mølck, GD Stewart, BJ Solomon, IA Parish, PJ Neeson, SJ Harrison, LM Kats, IG House, PK Darcy, PA Beavis
Nature Communications | NATURE PORTFOLIO | Published : 2021
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..
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Grants
Awarded by Gilead Sciences
Funding Acknowledgements
This work was funded by a Program Grant from the National Health and Medical Research Council (NHMRC, Grant number 1132373), an NHMRC Project grant (APP1122444), and a Synthego Genome Engineer Innovation Grant. J. Lai is supported by Cancer Research Institute Irvington Postdoctoral Fellowship (CRI Award #3530). P. A. Beavis was supported by a National Breast Cancer Foundation Fellowship (IECF-17-005; 2017-2020) and a Victorian Cancer Agency Mid-Career Fellowship (MCRF20011, 2021-current). I.G. House is supported by a Victorian Cancer Agency Early Career Fellowship (ECRF20017). P.K. Darcy is supported by an NHMRC Senior Research Fellowship (APP1136680). The authors wish to acknowledge the contribution of consumer representatives Karen Gill, Mike Rear, and Graeme Sissing for their contribution to the study and research direction of the laboratory.