@article{e2ff0e4af8064239bf08f1ffc7cd61b0,
title = "CRISPR/Cas9 mediated deletion of the adenosine A2A receptor enhances CAR T cell efficacy",
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.",
author = "Lauren Giuffrida and Kevin Sek and Henderson, {Melissa A.} and Junyun Lai and Chen, {Amanda X.Y.} and Deborah Meyran and Todd, {Kirsten L.} and Petley, {Emma V.} and Sherly Mardiana and Christina M{\o}lck and Stewart, {Gregory D.} and Solomon, {Benjamin J.} and Parish, {Ian A.} and Neeson, {Paul J.} and Harrison, {Simon J.} and Kats, {Lev M.} and House, {Imran G.} and Darcy, {Phillip K.} and Beavis, {Paul A.}",
note = "Funding Information: 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. Funding Information: S.J.H. declares the following competing interests: Consultancy: Amgen, Celgene, Novartis, Janssen-Cilag, Haemalogix, GSK. Research funding: Celgene, Janssen-Cilag, and Novartis. L.M.K declares the following conflicts: consultancy and research funding from Agios and Celgene. P.K.D. declares the following conflicts: research funding from Myeloid Therapeutics, Prescient Therapeutics, and Juno Therapeutics. P.A.B. declares the following conflicts: research funding from AstraZeneca and Gilead Sciences. The remaining authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = dec,
doi = "10.1038/s41467-021-23331-5",
language = "English",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}