Targeting the arginine metabolic brake enhances immunotherapy for leukaemia

Francis Mussai, Rachel Wheat, Evgenia Sarrou, Sarah Booth, Victoria Stavrou, Livingstone Fultang, Tracey Perry, Pamela Kearns, Paul Cheng, Karen Keehsan, Charles Craddock, Carmela De Santo

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)
233 Downloads (Pure)

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-NYESO 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. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalInternational Journal of Cancer
Early online date28 Nov 2018
DOIs
Publication statusPublished - 28 Nov 2018

Keywords

  • arginine
  • T
  • CTAG
  • AML
  • immunotherapy

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