Lenalidomide and pomalidomide potently interfere with induction of myeloid-derived suppressor cells in multiple myeloma
- 1 December 2020
- journal article
- research article
- Published by Wiley in British Journal of Haematology
- Vol. 191 (5), 784-795
- https://doi.org/10.1111/bjh.16881
Abstract
An increase in immunosuppressive myeloid-derived suppressor cells (MDSCs) is associated with disease progression and treatment resistance in multiple myeloma (MM). We investigated the mechanisms underlying MDSC induction, and sought to discover a strategy for prevention of MDSC induction in MM. Using a transwell co-culture system, four of nine examined human myeloma-derived cell lines (HMCLs) were potent in inducing monocytic (M)-MDSCs from normal peripheral blood mononuclear cells (PBMCs). As the results, we identified that secretion of C-C motif chemokine ligand 5 (CCL5) and macrophage migration inhibitory factor (MIF) by myeloma cells is a prerequisite for induction of MDSCs in MM. The immunomodulatory drug (IMiD) compounds, such as lenalidomide (LEN) and pomalidomide (POM), were identified as potent inhibitors of MDSC induction through bidirectional molecular effects of cereblon (CRBN)-dependent and -independent downregulation of CCL5 and MIF in myeloma cells; and downregulation of C-C motif chemokine receptor 5, a receptor for CCL5, and induction of interferon regulatory factor 8, a critical transcription factor for monocytic differentiation, in PBMCs. In the present study of the molecular mechanisms underlying MDSC induction, we identified a novel effect of LEN and POM of inhibiting MDSC inductionviaoverlapping regulatory effects in myeloma cells and normal PBMCs.Keywords
Funding Information
- National Cancer Center (26‐A‐4, 29‐A‐3)
- Ministry of Health, Labour and Welfare (JP16ck0106077h003, JP17ck0106348h0001, JP18ck0106348h0002, JP19ck0106348h0003)
- Celgene
- Japan Society for the Promotion of Science (J182004103)
This publication has 42 references indexed in Scilit:
- Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trialThe Lancet Oncology, 2019
- Myeloid-derived suppressor cells coming of ageNature Immunology, 2018
- Myeloid-Derived Suppressor Cells: Immune-Suppressive Cells That Impair Antitumor Immunity and Are Sculpted by Their EnvironmentJournal Of Immunology, 2018
- Systematic Literature Review and Network Meta-Analysis of Treatment Outcomes in Relapsed and/or Refractory Multiple MyelomaJournal of Clinical Oncology, 2017
- Mechanisms overseeing myeloid-derived suppressor cell production in neoplastic diseaseCancer Immunology, Immunotherapy, 2017
- Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trialThe Lancet, 2016
- Daratumumab, Lenalidomide, and Dexamethasone for Multiple MyelomaNew England Journal of Medicine, 2016
- Myeloid-derived suppressor cells: The green light for myeloma immune escapeBlood Reviews, 2016
- Elotuzumab Therapy for Relapsed or Refractory Multiple MyelomaNew England Journal of Medicine, 2015
- Chemotherapy-Derived Inflammatory Responses Accelerate the Formation of Immunosuppressive Myeloid Cells in the Tissue Microenvironment of Human Pancreatic CancerCancer Research, 2015