Lenalidomide increases human dendritic cell maturation in multiple myeloma patients targeting monocyte differentiation and modulating mesenchymal stromal cell inhibitory properties

Abstract

The use of Lenalidomide (LEN), to reverse tumor-mediated immune suppression and amplify multiple myeloma-specific immunity is currently being explored. Particularly, LEN effects on dendritic cells (DCs) are still unclear. In this study, we investigated the potential effect of LEN on DC differentiation and activity. DCs were differentiated either from CD14+ cells obtained from patients with multiple myeloma or from a human monocytic cell line.LEN, at the concentration range reached in vivo, significantly increased the median intensity expression of HLA-DR, CD86 and CD209 by DCs derived from both bone marrow and peripheral myeloma monocytes and enhanced the production of Interleukin-8, C-C motif chemokine ligand (CCL) 2, CCL5 and tumor necrosis factor-α. Consistently, LEN pre-treated DCs showed an increased ability to stimulate autologous CD3+ cell proliferation. LEN effect on dendritic differentiation was associated with the degradation of the Cereblon-related factors Ikaros and Aiolos. Moreover, we showed that LEN also blunted mesenchymal stromal cell inhibitory effect on dendritic differentiation, inhibiting Casein Kinase-1α levels. Finally, in vitro data were confirmed in ex vivo cultures obtained from relapsed myeloma patients treated with LEN, showing a significant increase of DC differentiation from peripheral blood monocytes.In conclusion, LEN increased the expression of mature dendritic markers both directly and indirectly and enhanced DC ability to stimulate T cell proliferation and to release chemokines. This suggests a new possible mechanism by which LEN could exert its anti-myeloma activity.

Ikaros family zinc finger 1 regulates dendritic cell development and function in humans

“…A similar pattern was seen in healthy donor DCs exposed to lenalidomide. The reduction in IL-12 secretion contrasted with reports showing that lenalidomide does not compromise IL-12 production from monocyte-derived DCs (moDCs) stimulated with CD40L 38 , 39 . However, moDCs are not dependent on IKZF1 for development 40 and in vitro stimulation with CD40L triggers IL-12 production through the non-canonical, nuclear factor (NF)-κB (p52/p100) pathway.…”

Standardization of sampling and sample preparation for analysis of human monocyte subsets in peripheral blood

“…Monocytes seem to be involved in the development of multiple myeloma bone disease, which is characterised by osteoclast activation and the absence of functioning osteoblasts, with the final effect being bone resorption [159,383,461,462]. Aiolos, a transcription factor of lymphocyte differentiation [463].…”

Checkpoint Inhibition in Myeloma: Opportunities and Challenges

“…The development of the IMiDs, thalidomide (Thal) and its analogs lenalidomide (Len) and pomalidomide (Pom), has led to a paradigm shift in the treatment of MM ( 100 ). IMiDs exert their immunological functions through several mechanisms, including proliferation and functional enhancement of NK/NKT cells, induction of T-cell co-stimulation and reduction of Treg activity, increased Th1 cytokine production, such as IL-2 and IFN-γ, anti-MM ADCC improvement and enhanced DC maturation and functions ( 101 – 103 ). The main molecular mechanism was recently elucidated showing that IMiDs bind Cereblon, causing a subsequent degradation of the transcriptional factors, Ikaros (IKZF1) and Aiolos (IKZF3) on both MM cells and T cells ( 104 ).…”