Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment

Abstract

Key Points• AML blasts have an arginase-dependent ability to inhibit T-cell proliferation and hematopoietic stem cells.• AML blasts have an arginase-dependent ability to modulate the polarization of monocytes.Acute myeloid leukemia (AML) is the most common acute leukemia in adults and the second most common frequent leukemia of childhood. Patients may present with lymphopenia or pancytopenia at diagnosis. We investigated the mechanisms by which AML causes pancytopenia and suppresses patients' immune response. This study identified for the first time that AML blasts alter the immune microenvironment through enhanced arginine metabolism. Arginase II is expressed and released from AML blasts and is present at high concentrations in the plasma of patients with AML, resulting in suppression of T-cell proliferation. We extended these results by demonstrating an arginase-dependent ability of AML blasts to polarize surrounding monocytes into a suppressive M2-like phenotype in vitro and in engrafted nonobese diabetic-severe combined immunodeficiency mice. In addition, AML blasts can suppress the proliferation and differentiation of murine granulocyte-monocyte progenitors and human CD34 1 progenitors. Finally, the study showed that the immunosuppressive activity of AML blasts can be modulated through smallmolecule inhibitors of arginase and inducible nitric oxide synthase, suggesting a novel therapeutic target in AML. The results strongly support the hypothesis that AML creates an immunosuppressive microenvironment that contributes to the pancytopenia observed at diagnosis. (Blood. 2013;122(5):749-758)

Modulation of L-Arginine-Arginase Metabolic Pathway Enzymes: Immunocytochemistry and mRNA Expression in Peripheral Blood and Tissue Levels in Head and Neck Squamous Cell Carcinomas in North East India

“…T-lymphocytes play an important role in cell mediated immunity; rely on their microenvironment for the supply of L-arginine. With the appearance of ARG, decreased T cell proliferation, low expression of specific T cell receptors and decreased production of cytokines have been observed (Mussai et al, 2013). Perioperative arginine-enriched nutrition significantly improved the long-term overall survival and long-term disease-specific survival in malnourished patients with head and neck cancer (Buijs et al, 2010).…”

IL-1 -releasing human acute myeloid leukemia blasts modulate natural killer cell differentiation from CD34+ precursors

“…This effect could be exerted either through cell-tocell contact or by the release of soluble factors. 6,7 Moreover, the conditioning regimen and/or the occurrence of GvHD may sustain an inflammatory response in the BM which may further interfere with the normal hematopoiesis. 8 Notably, inflammation has been associated with promotion and progression of solid tumors, and may correlate with a poor prognosis.…”

Detection of Pancytopenia Associated with Clinical Manifestation and Their Final Diagnosis

“…Arginase II is expressed and released from AML blasts and is present at high concentrations in the plasma of patients with AML, resulting in suppression of T-cell proliferation. In addition, AML blasts can suppress the proliferation and differentiation of murine granulocyte-monocyte progenitors and human CD34 + progenitors [16].  Hypersplenism: In hypersplenism there is peripheral pooling or trapping and destruction of cells in an enlarged spleen resulting in cytopenias.…”