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.
Highlights
The Immunomodulatory drugs (IMiDs®) are a group of therapeutic agents, Thalidomide-derivatives, including Lenalidomide (LEN) and Pomalidomide (POM)
We firstly demonstrated that hTERT-human mesenchymal stromal cell (hMSC) conditioned medium (CM) decreased dendritic cells (DCs) maturation marker expression in this in vitro system (Figure 6A); we found that LEN treatment reverted this effect, by increasing HLA-DR and CD86 (p calculated by Friedman test) (Figure 6B)
LEN exerts its immunomodulatory activity through several mechanisms of action on T and natural killer (NK) cells; [7, 32] few literature data reported the effect of LEN on DCs in the contest of the anti-MM activity and in the increased incidence of GvHD observed in patients treated with this drug [33]
Summary
The Immunomodulatory drugs (IMiDs®) are a group of therapeutic agents, Thalidomide-derivatives, including Lenalidomide (LEN) and Pomalidomide (POM). The development of these drugs represented a paradigm shift in the treatment of multiple myeloma (MM) [1, 2]. The loss of Ikaros and Aiolos is necessary and sufficient for LEN therapeutic effect [13] It has been reported a distinct CRBN substrate, Casein Kinase 1 alpha (CK1-α) that is ubiquitinated and degraded after LEN treatment in myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)) [14] and in MM, as reported by Manni S et al [15]
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