Lamarthée Baptiste, de Vassoigne Frédéric, Malard Florent, Stocker Nicolas, Boussen Inès, Médiavilla Clémence, Tang Ruoping, Fava Fanny, Garderet Laurent, Marjanovic Zora, Brissot Eolia, Mohty Mohamad, Gaugler Béatrice
Sorbonne Universités, UPMC Université Paris 06, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France.
AP-HP, Hôpital Saint-Antoine, Service d'Hématologie Clinique et Thérapie Cellulaire, Université Paris 06, Paris, France.
Oncoimmunology. 2018 Mar 19;7(7):e1444411. doi: 10.1080/2162402X.2018.1444411. eCollection 2018.
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.
多发性骨髓瘤（MM）源于骨髓（BM）中异常浆细胞的扩增。先前的研究表明，单核细胞在MM病理生理学中起关键作用。已经描述了一种表达6-磺基乳糖胺的树突状细胞群体（Slan-DCs），其在表型上与中间型和非经典单核细胞重叠。Slan-DCs代表一种循环和组织促炎性髓样细胞群体，已证明其在不同的癌症背景中发挥作用，并且具有显著的可塑性。在此，我们研究了MM患者骨髓和血液中的Slan-DCs。我们对54例新诊断的有症状MM患者、21例意义未明的单克隆丙种球蛋白病（MGUS）患者和24例缓解期MM患者的这些细胞进行了定量和功能分析。我们发现，与健康供体或MGUS患者相比，MM患者循环中的Slan-DCs显著减少，而CD14 + CD16 +中间型单核细胞在骨髓中积聚。此外，用Toll样受体7/8（TLR7/8）配体R848激活后，与健康供体相比，MM患者骨髓或外周血中产生白细胞介素-12（IL-12）的Slan-DCs减少。我们表明，MM细胞系或诊断时从患者分离的MM细胞能够抑制Slan-DCs产生IL-12，并使Slan-DCs的表型向中间型单核细胞样表型转变。最后，与MM细胞共培养的Slan-DCs降低了其诱导T细胞增殖和Th1极化的能力。我们得出结论，Slan-DCs代表MM发展中先前未被认识的参与者，可能是一个治疗靶点。
