Quantitative and functional alterations of 6-sulfo LacNac dendritic cells in multiple myeloma

ABSTRACT

Multiple myeloma (MM) results from expansion of abnormal plasma cells in the bone marrow (BM). Previous studies have shown that monocytes play a crucial role in MM pathophysiology. A 6-sulfo LacNAc-expressing population of dendritic cells (Slan-DCs) that overlaps with intermediate and non-classical monocytes in terms of phenotype has been described. Slan-DCs represent a circulating and tissue proinflammatory myeloid population which has been shown to play a role in different cancer contexts, and which exhibits a remarkable plasticity. Herein, we studied Slan-DCs from the BM and blood of MM patients. We performed quantitative and functional analyses of these cells from 54 patients with newly diagnosed, symptomatic MM, 21 patients with MGUS and 24 responding MM patients. We found that circulating Slan-DCs were significantly decreased in MM patients as compared to those of healthy donors or patients with MGUS, while CD14+CD16+ intermediate monocytes accumulate in the BM. Moreover, after activation with TLR7/8 ligand R848, IL-12-producing Slan-DCs from the BM or peripheral blood from MM patients were decreased as compared with healthy donors. We show that MM cell lines or MM cells isolated from patients at diagnosis were able to inhibit the production of IL-12 by Slan-DCs, as well as to shift the phenotype of Slan-DCs towards an intermediate monocyte-like phenotype. Finally, Slan-DCs that have been cultured with MM cells reduced their capacity to induce T cell proliferation and Th1 polarization. We conclude that Slan-DCs represent previously unrecognized players in MM development and may represent a therapeutic target.

KEYWORDS:

• antitumor T cell
• dendritic cells
• immunotherapy
• Immunosurveillance
• multiple myeloma
• Slan-DC

Conflict-of-interest disclosure

The authors declare no competing financial interests.

Acknowledgments

The authors thank Annie Munier from the LUMIC flow cytometry facility. MM thanks Prof. J.V. Melo (Adelaide, Australia) for critical reading of the manuscript. The authors also thank the Association for Training, Education and Research in Hematology, Immunology and Transplantation for the generous and continuous support to the research work. This work was supported by a grant from INCA (Emergence).

Authors' contribution

All authors listed on the manuscript have contributed substantially to this work: conception and design: M.M., B.L., F.M., B.G.; financial support: M.M.; administrative and logistical support: M.M.; provision of study materials and patient care: R.T., F.V.^, L.G., Z.M., E.B., F.M., M.M.; experimental work: B.L., F.D.V., N.S.; collection and assembly of clinical data: N.S., I.B., C.M., F.M.; data analysis and interpretation: B.L., F.M., B.G., M.M.; manuscript writing: B.L., B.G., M.M.; final approval of manuscript: all co-authors.

Additional information

Funding

Inca Emergence, National institute of Health and Medical Research (Inserm).