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Abstract
This study aimed to characterize different natural killer (NK) cell phenotypes on bone marrow and peripheral blood cells from acute myeloid leukemia (AML) patients and healthy donors (HDs). Our data show that CD56dimCD16− and CD56brightCD16− NK cells represent the predominant NK cell subpopulations in AML, while the CD56dimCD16+ NK cells are significantly reduced compared to HDs. Moreover, TIGIT+ and PVRIG+ cells cluster on the CD56dimCD16+ subset whereas CD39+ and CD38+ cells do so on CD56brightCD16− NK cells in AML. Furthermore, functional effects of (co-)blockade of TIGIT and CD39 or A2AR on NK cell functionality were analyzed. These experiments revealed that the single blockade of the TIGIT receptor results in an increased NK-92 cell-mediated killing of AML cells in vitro. Combined targeting of CD39 or A2AR significantly augments the anti-TIGIT-mediated lysis of AML cells. Our data indicate that distinct NK cell subsets in AML exhibit different immunosuppressive patterns (via the TIGIT/PVRIG receptors and the purinergic pathway). In summary, we conclude that TIGIT, CD39, and A2AR constitute relevant inhibitory checkpoints of NK cells in AML patients. A combinatorial blockade synergistically strengthens NK-92 cell-mediated cytotoxicity. As inhibitors of TIGIT, CD39, and A2AR are clinically available, studies on their combined use could be conducted in the near future.
Highlights
We focused on theexpression of the inhibitory receptors TIGIT, PVRIG, programmed cell death-1 (PD-1), and Lymphocyte activation gene 3 (LAG-3) as well as the ectonucleotidases Ectonucleoside triphosphate diphosphohydrolase-1 (CD39), Ecto-50 -nucleotidase (CD73), and Cyclic ADP-ribose hydrolase (CD38) and we investigated whether TIGIT blockade together with blockade of the purinergic signaling can reinvigorate natural killer (NK) cell-mediated killing of acute myeloid leukemia (AML) blasts
Expression of the receptors CD56 and CD16 was assessed on NK cells derived from the peripheral blood (PB, n = 15) and bone marrow (BM, n = 25) aspirates from patients with untreated newly diagnosed AML and compared to PB specimens of healthy donors (HD, n = 12)
CD56dim CD16− and CD56bright CD16− NK cells were significantly increased in AML patients compared to HDs
Summary
They possess an intrinsic selectivity and capacity to kill cancer cells without requiring prior sensitization, which is distinct from the effector T cells of the adaptive immune system. They establish a robust cytotoxic immune response much more rapidly than T cells and have the ability to recruit other adaptive responders [2,3]. These features make NK cells promising candidates for immunotherapeutic strategies in the treatment of cancer [3]. The CD56– CD16+ NK cells are defined as an unconventional NK cell subset increased in chronic infections and cancer and with significantly decreased effector functions [8,9,10]
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