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PMID: 19800576 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Cancer cell ·Vol. 16 ·No. 4 ·2009-10-06 ·Pages 309-23

Chauhan D, Singh AV, Brahmandam M, Carrasco R, Bandi M, Hideshima T, Bianchi G, Podar K, Tai YT, Mitsiades C, Raje N, Jaye DL, Kumar SK, Richardson P, Munshi N, Anderson KC

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.

MeSH Terms
Animals Antineoplastic Agents/pharmacology Apoptosis Bone Marrow Cells/drug effects,immunology,pathology Boronic Acids/pharmacology Bortezomib Case-Control Studies Cell Communication/drug effects Cell Proliferation Cell Survival Chemotaxis Coculture Techniques Cytokines/metabolism Dendritic Cells/drug effects,immunology,pathology Drug Resistance, Neoplasm Gene Expression Regulation, Neoplastic Humans Immunophenotyping Mice Mice, SCID Multiple Myeloma/drug therapy,genetics,immunology,pathology 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,metabolism Transplantation, Heterologous Tumor Cells, Cultured
Chemicals
Antineoplastic Agents Boronic Acids CPG-oligonucleotide Cytokines Oligodeoxyribonucleotides Protease Inhibitors Pyrazines Receptors, Immunologic Toll-Like Receptors Bortezomib Proteasome Endopeptidase Complex
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Chauhan Dharminder
The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Myeloma Research, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. [email protected]
Singh Ajita V
Brahmandam Mohan
Carrasco Ruben
Bandi Madhavi
Hideshima Teru
Bianchi Giada
Podar Klaus
Tai Yu-Tzu
Mitsiades Constantine
Raje Noopur
Jaye David L
Kumar Shaji K
Richardson Paul
Munshi Nikhil
Anderson Kenneth C
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2009.08.019
Email
[email protected]
Published
2009-10-06
Pages
309-23
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC2762396
Subset
IM
Grants
NCI NIH HHS · P01 CA078378-06A10007 · United States
NCI NIH HHS · P01-CA078378 · United States
NCI NIH HHS · R01CA050947 · United States
NCI NIH HHS · P01 CA078378-10 · United States
NCI NIH HHS · P01 CA078378 · United States
NCI NIH HHS · P50 CA100707-07 · United States
NCI NIH HHS · P01 CA155258 · United States
PHS HHS · P50100707 · United States
NCI NIH HHS · R01 CA050947 · United States
NCI NIH HHS · P50 CA100707 · United States
NCI NIH HHS · R01 CA050947-16 · United States
Databases
GEO
GSE17407
External Links
PubMed source DOI: 10.1016/j.ccr.2009.08.019 PMC Full Text View journal details
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