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

Abstract

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 þ 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.

Sodium valproate, a histone deacetylase inhibitor, augments the expression of cell-surface NKG2D ligands, MICA/B, without increasing their soluble forms to enhance susceptibility of human osteosarcoma cells to NK cell-mediated cytotoxicity

“…In this study, we showed that VPA elevated the expression of MICA and B on the surface of osteosarcoma cells and enhanced their susceptibility to the cytotoxicity of NK cells as reported with other tumor cells (6)(7)(8)(9)(10)(11). On the other hand, levels of soluble MICA and B were not changed or rather decreased in the presence of VPA.…”

“…HDAC inhibitors which alter the histone acetylation status have been shown to induce cell cycle arrest and apoptosis in various tumor cells (4,5). In addition, HDAC inhibitors stimulate the expression of cellsurface MICA and B on tumor cells to enhance cytotoxicity of NK cells and host immune surveillance against tumor cells (6)(7)(8)(9)(10)(11).…”

Natural killer cell immune escape in acute myeloid leukemia

“…83,99 All-transretinoic acid and the histone deacetylase inhibitor sodium valproate were repeatedly shown to induce NKG2D ligand expression in certain types of tumors, including AML, 44,100,101 leading to an improved sensitivity to NK cell-mediated killing. Promotors of myeloid cell differentiation trichostatin A and vitamin D3 were also shown to upregulate NKG2D ligands on AML cells.…”

Downregulation of matrix metalloproteinase-9 mRNA by valproic acid plays a role in inhibiting the shedding of MHC class I-related molecules A and B on the surface of human osteosarcoma cells

“…A number of studies have demonstrated that HDAC inhibitors stimulate the expression of cell surface MICA and MICB in a variety of tumors (12)(13)(14)(15). Valproic acid (VPA), a HDAC inhibitor, increases the expression of MICA and MICB on the surface of human osteosarcoma cells (16).…”