NOX2-dependent immunosuppression in chronic myelomonocytic leukemia

Authors:
Publisher website
Google Scholar
Abstract
Chronic myelomonocytic leukemia (CMML) is a myeloproliferative and myelodysplastic neoplasm with few treatment options and dismal prognosis. The role of natural killer (NK) cells and other antileukemic lymphocytes in CMML is largely unknown. We aimed to provide insight into the mechanisms of immune evasion in CMML with a focus on immunosuppressive reactive oxygen species (ROS) formed by the myeloid cell NADPH oxidase-2 (NOX2). The dominant population of primary human CMML cells was found to express membrane-bound NOX2 and to release ROS, which, in turn, triggered extensive PARP-1–dependent cell death in cocultured NK cells, CD8+ T effector memory cells, and CD8+ T effector cells. Inhibitors of ROS formation and scavengers of extracellular ROS prevented CMML cell-induced lymphocyte death and facilitated NK cell degranulation toward Ab-coated, primary CMML cells. In patients with CMML, elevation of immature cell counts (CD34+) in blood was associated with reduced expression of several NK cell-activating receptors. We propose that CMML cells may use extracellular ROS as a targetable mechanism of immune escape.
Funding Information
  • Swedish Cancer Society
  • Swedish Research Council
  • Assar Gabrielsson Foundation
  • The Swedish Society of Medicine
  • Torsten and Ragnar Soüderberg's Foundation
  • Inga-Britt and Arne Lundberg Research Foundation
  • Sahlgrenska University Hospital
  • Sahlgrenska Academy at University of Gothenburg
  • Department of Hematology at Sahlgrenska University Hospital
  • Skåne University Hospital

This publication has 38 references indexed in Scilit: