Effective in vivo induction of NKG2D ligands in acute myeloid leukaemias by all-trans-retinoic acid or sodium valproate

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Engagement of NKG2D by their ligands (NKG2D-L), as the human major histocompatibility complex class I-related molecules MIC-A and the UL16-binding proteins, on cytolytic lymphocytes leads to the enhancement of antitumour effector functions. These ligands are missing or expressed at very low levels on leukaemic cells; furthermore, they can be shed by tumour cells and inhibit cytolytic activity of lymphocytes. Herein, we show that in vivo administration of all-trans-retinoic acid (ATRA) or the histone deacetylase inhibitor sodium valproate (VPA) to patients affected with acute myeloid leukaemia (AML) M3 or M1 respectively, leads to the induction of transcription and expression of NKG2D-L at the surface of leukaemic cells. Apparently, no detectable shedding of the soluble form of these molecules was found in patients' sera. Conversely, AML blasts from patients treated with chemotherapy not including ATRA or VPA did not show any induction of NKG2D-L transcription. Furthermore, upon therapy with ATRA or VPA, leukaemic blasts become able to trigger lytic granule exocytosis by autologous CD8(+) T and natural killer lymphocytes, as shown by CD107a mobilization assay, followed by leukaemic cell lysis. These findings indicate that ATRA and VPA may contribute to the activation of cytolytic effector lymphocytes in vivo, possibly enhancing their anti-leukaemic effect.