Journal article

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

Lauren Giuffrida, Kevin Sek, Melissa A Henderson, Junyun Lai, Amanda XY Chen, Deborah Meyran, Kirsten L Todd, Emma Petley, Sherly Mardiana, Christina Molck, Gregory D Stewart, Benjamin J Solomon, Ian A Parish, Paul J Neeson, Simon J Harrison, Lev M Kats, Imran G House, Phillip K Darcy, Paul A Beavis

NATURE COMMUNICATIONS | NATURE RESEARCH | 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 National Health and Medical Research Council (NHMRC)


Awarded by NHMRC


Awarded by Cancer Research Institute Irvington Postdoctoral Fellowship (CRI)


Awarded by National Breast Cancer Foundation Fellowship (2017-2020)


Awarded by Victorian Cancer Agency Mid-Career Fellowship


Awarded by Victorian Cancer Agency Early Career Fellowship


Awarded by NHMRC Senior Research Fellowship


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.