Lenalidomide increases human dendritic cell maturation in multiple myeloma patients targeting monocyte differentiation and modulating mesenchymal stromal cell inhibitory properties
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Federica Costa1, Rosanna Vescovini1, Marina Bolzoni1, Valentina Marchica1, Paola Storti1, Denise Toscani1, Fabrizio Accardi1,2, Laura Notarfranchi1,2, Benedetta Dalla Palma1,2, Cristina Manferdini3, Sabrina Manni4, Giannalisa Todaro1, Gina Lisignoli3, Francesco Piazza4, Franco Aversa1,2 and Nicola Giuliani1,2
1Department of Medicine and Surgery, University of Parma, Parma, Italy
2Hematology and BMT Center, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
3Laboratory of Immunorheumatology and Tissue Regeneration, Istituto Ortopedico Rizzoli, Bologna, Italy
4Department of Medicine, Hematology Branch, University of Padova and Venetian Institute of Molecular Medicine, Padova, Italy
Nicola Giuliani, email: email@example.com
Keywords: multiple myeloma, dendritic cells, lenalidomide, mesenchymal stromal cells, immunomodulation
Received: December 14, 2016 Accepted: May 10, 2017 Published: May 23, 2017
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.
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