E-cadherin expression on multiple myeloma cells activates tumor-promoting properties in plasmacytoid DCs
Enguang Bi, … , Yong-Jun Liu, Qing Yi
Enguang Bi, … , Yong-Jun Liu, Qing Yi
Published November 1, 2018; First published October 2, 2018
Citation Information: J Clin Invest. 2018;128(11):4821-4831. https://doi.org/10.1172/JCI121421.
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Research Article Immunology Therapeutics

E-cadherin expression on multiple myeloma cells activates tumor-promoting properties in plasmacytoid DCs

Abstract

Plasmacytoid dendritic cells (pDCs) play a key role in antiviral responses by producing type-1 IFNs. However, recent studies showed that pDCs induce immune suppression and promote tumor growth in human ovarian cancer and myeloma. The molecular mechanisms underlying pDC acquisition of these properties are unknown. Here we show that human pDCs activated by CpG inhibited growth and induced apoptosis in myeloma cells via secreted IFN-α, but direct contact with myeloma cells converted pDCs into tumor-promoting cells by suppressing pDC IFN-α production. E-cadherin, expressed on both myeloma cells and pDCs, mediated these effects via a homophilic interaction — activation of E-cadherin signaling upregulated and activated TNFAIP3 to interact with TLR9, resulting in TLR9 ubiquitination and degradation, and inhibition of IFN-α production in pDCs. These findings were supported by an in vivo study in which pDC depletion induced tumor regression and better survival in the Vk*MYC myeloma mouse model. Furthermore, IFNAR1 expression level positively correlated to overall survival of patients with multiple myeloma (MM), and the IFN-α level in patient bone marrow was significantly lower than that in marrow of healthy individuals. This study reveals a novel mechanism underlying how MM tumors educate pDCs in their microenvironment and provides new targets for improving the treatment of MM.

Authors

Enguang Bi, Rong Li, Laura C. Bover, Haiyan Li, Pan Su, Xingzhe Ma, Chunjian Huang, Qiang Wang, Lintao Liu, Maojie Yang, Zhijuan Lin, Jianfei Qian, Weijun Fu, Yong-Jun Liu, Qing Yi

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Figure 1

MM cell–conditioned pDCs promote tumor growth in vivo.

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MM cell–conditioned pDCs promote tumor growth in vivo. BDCA2-DTR mice (n...
BDCA2-DTR mice (n = 12) and WT littermates (n = 12) were injected i.p. with DT (100 ng/mouse) 1 day before i.v. injection of Vk*MYC myeloma cells. DT was administrated every other day for 5 times. Blood was collected weekly via tail vein for detection of the monoclonal band (M-band) using serum protein electrophoresis. Shown are (A) the positive ratio of mice with M-band, (B) quantified relative M-band density, and (C) mouse survival. (D) Splenocytes from tumor-free (Ctrl) or myeloma-bearing (MM) WT mice were stimulated with CpG and blocked with Brefeldin A. IFN-α production was detected in pDC cells by FACS and quantified. (E) Overall survival of patients with MM based on high IFNAR1 (IFNAR1hi) and low IFNAR1 (IFNAR1lo) gene expression (GSE2658 data set). (F) Levels of IFN-α expression in bone marrow from healthy donors (n = 5; HD) and patients with MM (n = 100). MM (ARP1 and MM.1S) cells were cultured alone or in direct (D) or transwell (T) coculture with pDCs (freshly sorted human pDCs from blood of healthy donors; the same thereafter unless otherwise stated) with or without CpG. (G) The number of live MM cells and (H) MM cell apoptosis are shown. Number of live MM.1S cells (I) and ARP1 cells (J) cultured alone, or in direct (D) or transwell (T) coculture with pDCs with or without CpG, in the presence or absence of IFN-α–neutralizing mAb. Experiments were performed 3 times in A–D and G–I. Statistical significance was obtained by Student’s t test, and Bonferroni’s corrected significance level was used when more than 2 groups were included in an analysis. *P < 0.05, **P < 0.01.