Functional interaction of plasmacytoid dendritic cells with multiple myeloma cells: a therapeutic target

Dharminder Chauhan, Ajita V Singh, Mohan Brahmandam, Ruben Carrasco, Madhavi Bandi, Teru Hideshima, Giada Bianchi, Klaus Podar, Yu-Tzu Tai, Constantine Mitsiades, Noopur Raje, David L Jaye, Shaji K Kumar, Paul Richardson, Nikhil Munshi, Kenneth C Anderson

Research output: Journal article (peer-reviewed)Journal article

241 Citations (Scopus)

Abstract

Multiple myeloma (MM) remains incurable despite novel therapies, suggesting the need for further identification of factors mediating tumorigenesis and drug resistance. Using both in vitro and in vivo MM xenograft models, we show that plasmacytoid dendritic cells (pDCs) in the bone marrow (BM) microenvironment both mediate immune deficiency characteristic of MM and promote MM cell growth, survival, and drug resistance. Microarray, cell signaling, cytokine profile, and immunohistochemical analysis delineate the mechanisms mediating these sequelae. Although pDCs are resistant to novel therapies, targeting toll-like receptors with CpG oligodeoxynucleotides both restores pDC immune function and abrogates pDC-induced MM cell growth. Our study therefore validates targeting pDC-MM interactions as a therapeutic strategy to overcome drug resistance in MM.

Original languageEnglish
Pages (from-to)309-323
Number of pages15
JournalCancer Cell
Volume16
Issue number4
DOIs
Publication statusPublished - 06 Oct 2009
Externally publishedYes

Keywords

  • Animals
  • Antineoplastic Agents/pharmacology
  • Apoptosis
  • Bone Marrow Cells/drug effects
  • Boronic Acids/pharmacology
  • Bortezomib
  • Case-Control Studies
  • Cell Communication/drug effects
  • Cell Proliferation
  • Cell Survival
  • Chemotaxis
  • Coculture Techniques
  • Cytokines/metabolism
  • Dendritic Cells/drug effects
  • Drug Resistance, Neoplasm
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunophenotyping
  • Mice
  • Mice, SCID
  • Multiple Myeloma/drug therapy
  • Oligodeoxyribonucleotides/pharmacology
  • Protease Inhibitors/pharmacology
  • Proteasome Endopeptidase Complex/metabolism
  • Pyrazines/pharmacology
  • Receptors, Immunologic/metabolism
  • Signal Transduction/drug effects
  • T-Lymphocytes/immunology
  • Time Factors
  • Toll-Like Receptors/drug effects
  • Transplantation, Heterologous
  • Tumor Cells, Cultured

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