Mussai F, Wheat R, Sarrou E, et al. – In patients with acute myeloid leukemia (AML) who received azacitidine (AZA) and vorinostat (VOR) treatment in a phase 2 trial, researchers investigated the impact of failing to address the arginine metabolic microenvironment on immune-modulatory epigenetic therapy or CAR-T cytotoxicity against leukemic blasts. They found that blasts increased expression of Cancer-Testis Antigens (MAGE, RAGE, LAGE, SSX2 and TRAG3), which can be identified by circulating antigen-specific T cells. Although these unmasked antigens could activate T cells, T cell exhaustion resulted from a metabolic brake due to low arginine microenvironment created by AML blast Arginase II activity. Antigen stimulation under low arginine conditions caused T cells to show impaired proliferation, decreased IFN-γ release, and PD-1 up-regulation. The proliferation and cytotoxicity of anti-NY-ESO T cells against AZA/VOR treated AML blasts was found to be enhanced in response to inhibition of arginine metabolism, which can also increase anti-CD33 Chimeric Antigen Receptor-T cell cytotoxicity. Thus, a key adjunct to immunotherapy could be an estimation of plasma arginine levels together with therapeutic targeting of arginase activity in AML blasts.