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 5

A20 degrades TLR9 protein in pDCs induced by CDH1 activation.

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A20 degrades TLR9 protein in pDCs induced by CDH1 activation. Concentrat...
Concentration of IFN-α secreted by pDCs (A) in direct coculture with MM (ARP1) cells or (B) induced by CDH1 agonist antibody in the presence of different doses of lactacystin (LA). (C) Immunoprecipitation assay and (D) mass spectrometry showing TLR9 ubiquitination in Gen2.2 (plus CpG) in 1-hour culture with Ig control or CDH1 agonist antibody. Proteins with at least 2-fold increase between CDH1 agonist antibody and control IgG group are shown in (D). Western blot showing (E) expression of A20 in Gen2.2 cells induced by CpG and CDH1 agonist antibody, or (F) expression of TLR9 and A20 in 293T cells cotransfected with TLR9 plasmid and A20 plasmid. Cells were collected 24 hours after transfection and subject to analysis. (G) Immunoprecipitation assay showing the interaction of TLR9 and A20 in 293T cells cotransfected with TLR9 plasmid, A20 plasmid, and β-catenin plasmid. Cells were harvested 24 hours after transfection and subjected to analysis. pDCs were transfected with control siRNA or A20 siRNA for 24 hours to knockdown A20 (H), and (I) the concentration of IFN-α secreted or (J) expression of TLR9 by control (Ctrl siRNA) or A20 knockdown (A20 siRNA) was determined by using pDCs cocultured with or without MM (ARP1) cells in the presence of CpG. 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.