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 3

MM cells inhibit pDC IFN-α production by downregulating pDC TLR9 expression.

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MM cells inhibit pDC IFN-α production by downregulating pDC TLR9 express...
pDCs were cultured alone or in direct coculture with MM (MM.1S or ARP1) cells in the presence of CpG, and supernatant was collected at the indicated time points for measurement of (A) IFN-β and (B) IFN-α. Expression of (C) TLR9 or (D) TLR7 by (CD123+CD138–) pDCs cultured alone or in direct or transwell (TW) coculture with MM (ARP1) cells in the presence of CpG for 16 hours. Gen2.2 cells were directly cocultured with MM (ARP1 or MM.1) cells with or without CpG for 16 hours, followed by depletion of MM cells with CD138+ beads. Gen2.2 cells were collected and subjected to (E) Western blot or (F) qPCR analyses for the expression of TLR9/7 and MyD88. Flow cytometry analysis showing the expression levels of TLR9 in (G) human pDCs from healthy donors (n = 5) or patients with MM (n = 5), or (H) murine pDCs from tumor-free (control, Ctrl) or Vk*MYC myeloma-bearing B6 mice (n = 5, each group). All experiments were performed 3 times. 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.