Targeting the arginine metabolic brake enhances immunotherapy for leukaemia

Mussai, F. et al. (2019) Targeting the arginine metabolic brake enhances immunotherapy for leukaemia. International Journal of Cancer, 145(8), pp. 2201-2208. (doi: 10.1002/ijc.32028) (PMID:30485425) (PMCID:PMC6767531)

Abstract

Therapeutic approaches which aim to target Acute Myeloid Leukaemia through enhancement of patients’ immune responses have demonstrated limited efficacy to date, despite encouraging preclinical data. Examination of AML patients treated with azacitidine (AZA) and vorinostat (VOR) in a Phase II trial, demonstrated an increase in the expression of Cancer‐Testis Antigens (MAGE, RAGE, LAGE, SSX2 and TRAG3) on blasts and that these can be recognised by circulating antigen‐specific T cells. Although the T cells have the potential to be activated by these unmasked antigens, the low arginine microenvironment created by AML blast Arginase II activity acts a metabolic brake leading to T cell exhaustion. T cells exhibit impaired proliferation, reduced IFN‐γ release and PD‐1 up‐regulation in response to antigen stimulation under low arginine conditions. Inhibition of arginine metabolism enhanced the proliferation and cytotoxicity of anti‐NY‐ESO T cells against AZA/VOR treated AML blasts, and can boost anti‐CD33 Chimeric Antigen Receptor‐T cell cytotoxicity. Therefore, measurement of plasma arginine concentrations in combination with therapeutic targeting of arginase activity in AML blasts could be a key adjunct to immunotherapy.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Keeshan, Dr Karen
• Authors: Mussai, F., Wheat, R., Sarrou, E., Booth, S., Stavrou, V., Fultang, L., Perry, T., Kearns, P., Cheng, P., Keeshan, K., Craddock, C., and De Santo, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: International Journal of Cancer
• Publisher: John Wiley and Sons
• ISSN: 0020-7136
• ISSN (Online): 1097-0215
• Published Online: 28 November 2018
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in International Journal of Cancer 145(8):2201-2208
• Publisher Policy: Reproduced under a Creative Commons License