Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells: clinical application

Abstract

Summary Thalidomide and immunomodulatory drugs (IMiDs), which target multiple myeloma (MM) cells and the bone marrow microenvironment, can overcome drug resistance. These agents also have immunomodulatory effects. Specifically, we have reported that thalidomide increased serum interleukin‐2 (IL‐2) levels and natural killer (NK) cell numbers in the peripheral blood of responding MM patients. In this study, we investigated the mechanisms whereby IMiDs augment NK cell cytotoxicity. NK cytotoxicity and antibody‐dependent cell‐mediated cytotoxicity (ADCC) of peripheral blood mononuclear cells cultured with IMiDs were examined in the presence or absence of anti‐IL‐2 antibody, ciclosporin A or depletion of CD56‐positive cells. IMiDs‐induced signalling pathways, triggering IL‐2 transcription in T cells, were also delineated. IMiDs facilitated the nuclear translocation of nuclear factor of activated T cells‐2 and activator protein‐1 via activation of phosphoinositide‐3 kinase signalling, with resultant IL‐2 secretion. IMiDs enhanced both NK cell cytotoxicity and ADCC induced by triggering IL‐2 production from T cells. These studies defined the mechanisms whereby IMiDs trigger NK cell‐mediated tumour‐cell lysis, further supporting their therapeutic use in MM.

Immunomodulatory drugs stimulate natural killer‐cell function, alter cytokine production by dendritic cells, and inhibit angiogenesis enhancing the anti‐tumour activity of rituximab in vivo

“…As shown previously by other investigators, IMiDs have direct anti-myeloma effects and can overcome resistance to conventional therapy (Hideshima et al, 2000). It was demonstrated that in multiple myeloma, IMiDs increase the NK-cell pool by triggering the release of IL-2 secretion by T (Hayashi et al, 2005). There is evidence to support that lenalidomide enhances the expansion of NK and T cells in patients with multiple myeloma and that cells activated in the presence of lenalidomide secrete IFN-c (Chang et al, 2006).…”

Lenalidomide as salvage therapy after allo-SCT for multiple myeloma is effective and leads to an increase of activated NK (NKp44+) and T (HLA-DR+) cells

“…This confirms previous observations of activation of NK and T cells after therapy with thalidomide or lenalidomide. 14,15 This immunostimulating effect of lenalidomide might be an important mechanism of its anti-myeloma activity beside its anti-angiogenetic properties and its apoptotic effect. The increase of T-regulatory cells in myeloma patients remains unclear, 16 and after allo-SCT, Tregulatory cells seem to have a GVHD-protecting effect.…”

Inhibition of metastatic potential in colorectal carcinoma in vivo and in vitro using immunomodulatory drugs (IMiDs)

“…It is important to understand that the induction of tumour cytotoxicity can also be a result of an enhanced immunological responses caused by IMiDs. The increased proliferation of a number of immune cell groups, including CD4-positive and CD8-positive cells in addition to the initiation of dendritic cell function, can lead to the activation of natural killer cells that drive cytophagy and cytolysis (Davies et al, 2001;Hayashi et al, 2005;Wu et al, 2008).…”