The Role of Histone deacetylase (HDAC) Inhibitors and Cytokine-induced Killer Cell (CIK) in Multiple Myeloma

Abstract

Multiple myeloma (MM) is a complex blood neoplasm marked by abnormal plasma cell growth due to genetic and epigenetic changes. Although treatments have improved, MM remains largely incurable, often developing resistance to drugs. Recent research focuses on histone deacetylases (HDACs), with HDAC inhibitors (HDACis) showing potential in enhancing natural killer (NK) cell effectiveness. Studies also suggest promising results with cytokine-induced killer (CIK) cell immunotherapy. The combination of HDACis and CIK cell therapy in clinical trials could potentially improve treatment outcomes for MM.<br /> This dissertation explores the role of HDACis and CIK cell immunotherapy in MM by investigating two primary research objectives: 1) the respective roles of HDACis and CIK cell immunotherapy in the development and progression of MM; 2) the potential benefits of combining HDACis with CIK cell immunotherapy in the treatment of MM and the molecular mechanisms behind this interaction. <br /> We examined clinically relevant HDACis (panobinostat/LBH589 and romidepsin) alongside CIK cells derived from peripheral blood mononuclear cells across diverse MM cell lines (U266, RPMI8226, OPM-2 and NCI-H929). Utilizing various in vitro methodologies, we investigated how HDACis enhance CIK cell lysis of myeloma cells through NKG2D/NKG2D ligand interactions. <br /> The combination of CIK cells with HDACis significantly enhances their ability to kill MM cells, mainly by increasing apoptosis and altering immune signaling molecules like interferon-γ (IFN-γ) and granzyme B. HDACis also boost the expression of proteins MICA/B and ULBP2, vital for NKT cell-driven antitumor effects. These effects were confirmed by blocking the NKG2D receptor in CIK cells, which supports the synergistic action of HDACis and CIK cells in targeting MM. <br /> Our analyses provide sufficient evidence to consider this clinically forgotten instance (HDACis-CIK cell combination) as a therapeutic priority for MM treatment. Furthermore, we suggest that NKG2D/NKG2D-ligand interactions activating NK/NKT cells may contribute to enhanced myeloma cell lysis in response to HDACis treatment by CIK cells.