A2AR eGFP reporter mouse enables elucidation of A2AR expression dynamics during anti-tumor immune responses

Kirsten L. Todd (), Junyun Lai, Kevin Sek, Yu-Kuan Huang, Dane M. Newman, Emily B. Derrick, Hui-Fern Koay, Dat Nguyen, Thang X. Hoang, Emma V. Petley, Cheok Weng Chan, Isabelle Munoz, Imran G. House, Joel N. Lee, Joelle S. Kim, Jasmine Li, Junming Tong, Maria N. de Menezes, Christina M. Scheffler, Kah Min Yap, Amanda X. Y. Chen, Phoebe A. Dunbar, Brandon Haugen, Ian A. Parish, Ricky W. Johnstone, Phillip K. Darcy and Paul A. Beavis ()
Additional contact information
Kirsten L. Todd: Peter MacCallum Cancer Centre
Junyun Lai: Peter MacCallum Cancer Centre
Kevin Sek: Peter MacCallum Cancer Centre
Yu-Kuan Huang: Peter MacCallum Cancer Centre
Dane M. Newman: The University of Melbourne
Emily B. Derrick: Peter MacCallum Cancer Centre
Hui-Fern Koay: University of Melbourne
Dat Nguyen: Peter MacCallum Cancer Centre
Thang X. Hoang: Peter MacCallum Cancer Centre
Emma V. Petley: Peter MacCallum Cancer Centre
Cheok Weng Chan: Peter MacCallum Cancer Centre
Isabelle Munoz: Peter MacCallum Cancer Centre
Imran G. House: Peter MacCallum Cancer Centre
Joel N. Lee: Peter MacCallum Cancer Centre
Joelle S. Kim: Peter MacCallum Cancer Centre
Jasmine Li: Peter MacCallum Cancer Centre
Junming Tong: Peter MacCallum Cancer Centre
Maria N. de Menezes: Peter MacCallum Cancer Centre
Christina M. Scheffler: Peter MacCallum Cancer Centre
Kah Min Yap: Peter MacCallum Cancer Centre
Amanda X. Y. Chen: Peter MacCallum Cancer Centre
Phoebe A. Dunbar: Peter MacCallum Cancer Centre
Brandon Haugen: Peter MacCallum Cancer Centre
Ian A. Parish: Peter MacCallum Cancer Centre
Ricky W. Johnstone: The University of Melbourne
Phillip K. Darcy: Peter MacCallum Cancer Centre
Paul A. Beavis: Peter MacCallum Cancer Centre

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract There is significant clinical interest in targeting adenosine-mediated immunosuppression, with several small molecule inhibitors having been developed for targeting the A2AR receptor. Understanding of the mechanism by which A2AR is regulated has been hindered by difficulty in identifying the cell types that express A2AR due to a lack of robust antibodies for these receptors. To overcome this limitation, here an A2AR eGFP reporter mouse is developed, enabling the expression of A2AR during ongoing anti-tumor immune responses to be assessed. This reveals that A2AR is highly expressed on all tumor-infiltrating lymphocyte subsets including Natural Killer (NK) cells, NKT cells, γδ T cells, conventional CD4+ and CD8+ T lymphocytes and on a MHCIIhiCD86hi subset of type 2 conventional dendritic cells. In response to PD-L1 blockade, the emergence of PD-1+A2AR- cells correlates with successful therapeutic responses, whilst IL-18 is identified as a cytokine that potently upregulates A2AR and synergizes with A2AR deficiency to improve anti-tumor immunity. These studies provide insight into the biology of A2AR in the context of anti-tumor immunity and reveals potential combination immunotherapy approaches.

Date: 2023
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DOI: 10.1038/s41467-023-42734-0

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