RT Journal Article
SR Electronic
T1 The Immune Checkpoint Modulator OX40 and Its Ligand OX40L in NK-Cell Immunosurveillance and Acute Myeloid Leukemia
JF Cancer Immunology Research
JO Cancer Immunol Res
FD American Association for Cancer Research
SP 209
OP 221
DO 10.1158/2326-6066.CIR-17-0212
VO 6
IS 2
A1 Nuebling, Tina
A1 Schumacher, Carla Emilia
A1 Hofmann, Martin
A1 Hagelstein, Ilona
A1 Schmiedel, Benjamin Joachim
A1 Maurer, Stefanie
A1 Federmann, Birgit
A1 Rothfelder, Kathrin
A1 Roerden, Malte
A1 Dörfel, Daniela
A1 Schneider, Pascal
A1 Jung, Gundram
A1 Salih, Helmut Rainer
YR 2018
UL http://cancerimmunolres.aacrjournals.org/content/6/2/209.abstract
AB The TNF receptor family member OX40 promotes activation and proliferation of T cells, which fuels efforts to modulate this immune checkpoint to reinforce antitumor immunity. Besides T cells, NK cells are a second cytotoxic lymphocyte subset that contributes to antitumor immunity, particularly in leukemia. Accordingly, these cells are being clinically evaluated for cancer treatment through multiple approaches, such as adoptive transfer of ex vivo expanded polyclonal NK cells (pNKC). Here, we analyzed whether and how OX40 and its ligand (OX40L) influence NK-cell function and antileukemia reactivity. We report that OX40 is expressed on leukemic blasts in a substantial percentage of patients with acute myeloid leukemia (AML) and that OX40 can, after stimulation with agonistic OX40 antibodies, mediate proliferation and release of cytokines that act as growth and survival factors for the leukemic cells. We also demonstrate that pNKC differentially express OX40L, depending on the protocol used for their generation. OX40L signaling promoted NK-cell activation, cytokine production, and cytotoxicity, and disruption of OX40–OX40L interaction impaired pNKC reactivity against primary AML cells. Together, our data implicate OX40/OX40L in disease pathophysiology of AML and in NK-cell immunosurveillance. Our findings indicate that effects of the OX40–OX40L receptor–ligand system in other immune cell subsets and also malignant cells should be taken into account when developing OX40-targeted approaches for cancer immunotherapy. Cancer Immunol Res; 6(2); 209–21. ©2018 AACR.