Functional interaction of plasmacytoid dendritic cells with multiple myeloma cells: a therapeutic target.
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.
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. dharminder_chauhan@dfci.harvard.edu
Dharminder
D
Chauhan
Ajita V
AV
Singh
Mohan
M
Brahmandam
Ruben
R
Carrasco
Madhavi
M
Bandi
Teru
T
Hideshima
Giada
G
Bianchi
Klaus
K
Podar
Yu-Tzu
YT
Tai
Constantine
C
Mitsiades
Noopur
N
Raje
David L
DL
Jaye
Shaji K
SK
Kumar
Paul
P
Richardson
Nikhil
N
Munshi
Kenneth C
KC
Anderson
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D016022:Case-Control Studies; D002450:Cell Communication / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival; D002633:Chemotaxis; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016130:Immunophenotyping; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D051193:Toll-Like Receptors / Q000187:drug effects / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001897:Boronic Acids; C408982:CPG-oligonucleotide; D016207:Cytokines; D009838:Oligodeoxyribonucleotides; D011480:Protease Inhibitors; D011719:Pyrazines; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex