The immunomodulatory-drug, lenalidomide, sustains and enhances interferon-α production by human plasmacytoid dendritic cells
Received 22 February 2019
Accepted for publication 31 May 2019
Published 12 July 2019 Volume 2019:10 Pages 217—226
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Colin Mak
Peer reviewer comments 3
Editor who approved publication: Dr Martin Bluth
Kayoko Kibata,1 Tomoki Ito,1 Muneo Inaba,1 Akihiro Tanaka,1 Ryoichi Iwata,2 Noriko Inagaki-Katashiba,1 Vien Phan,1 Atsushi Satake,1 Shosaku Nomura1
1Kansai Medical University, First Department of Internal Medicine, Osaka, Japan; 2Kansai Medical University, Department of Neurosurgery, Osaka, Japan
Background: Lenalidomide (LEN), an immunomodulatory drug (IMiD), is currently used for treatment of multiple myeloma (MM). LEN potentiates T cell and natural killer cell functions. However, the cellular and molecular mechanisms underlying the immunomodulatory effects of LEN remain unclear. We focused on the effects of LEN on human plasmacytoid dendritic cells (pDCs), which are the major source of interferon (IFN)-α in the blood and play a central role in innate immune responses.
Results: We found that bortezomib, a proteasome inhibitor used to treat MM, killed pDCs but that 0.1–3 μM LEN (covering clinical plasma concentration range) did not affect pDC survival or CD86 expression. Bortezomib inhibited pDC-derived IFN-α production in a dose-dependent fashion, but 0.1–3 μM LEN sustained pDC-derived IFN-α production when stimulated with an optimal concentration of CpG-ODN 2216 (3 μM). In pDCs stimulated with a low concentration of CpG-ODN (0.1 μM), LEN enhanced IFN-α production. These results indicated that LEN, when used at a clinically relevant concentration, can potentially enhance IFN-α production by pDCs.
Conclusion: Collectively, our findings unveiled a novel target of LEN and extend the repertoire of the drug’s known immunomodulatory effects. These effects may explain the low incidence of herpes zoster viral infection observed during LEN treatment compared with bortezomib treatment. LEN may function as an IMiD affecting a wide array of immune cells, including pDCs, leading to amplification of a positive immune axis able to eliminate MM cells.
Keywords: lenalidomide, IMiDs, plasmacyotid DCs, type I IFNs, multiple myeloma
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