CD28-mediated regulation of multiple myeloma cell proliferation and survival.
Although interactions with bone marrow stromal cells are essential for multiple myeloma (MM) cell survival, the specific molecular and cellular elements involved are largely unknown, due in large part to the complexity of the bone marrow microenvironment itself. The T-cell costimulatory receptor CD28 is also expressed on normal and malignant plasma cells, and CD28 expression in MM correlates significantly with poor prognosis and disease progression. In contrast to T cells, activation and function of CD28 in myeloma cells is largely undefined. We have found that direct activation of myeloma cell CD28 by anti-CD28 mAb alone induces activation of PI3K and NFkappaB, suppresses MM cell proliferation, and protects against serum starvation and dexamethasone (dex)-induced cell death. Coculture with dendritic cells (DCs) expressing the CD28 ligands CD80 and CD86 also elicits CD28-mediated effects on MM survival and proliferation, and DCs appear to preferentially localize within myeloma infiltrates in primary patient samples. Our findings suggest a previously undescribed myeloma/DC cell-cell interaction involving CD28 that may play an important role in myeloma cell survival within the bone marrow stroma. These data also point to CD28 as a potential therapeutic target in the treatment of MM.
Bahlis
Nizar J
NJ
Department of Microbiology and Immunology, University of Miami School of Medicine, FL, USA.
King
Anne M
AM
Kolonias
Despina
D
Carlson
Louise M
LM
Liu
Hong Yu
HY
Hussein
Mohamad A
MA
Terebelo
Howard R
HR
Byrne
Gerald E
GE
Levine
Bruce L
BL
Boise
Lawrence H
LH
Lee
Kelvin P
KP
D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen / Q000096:biosynthesis; D001854:Bone Marrow Cells / Q000166:cytology; D018106:CD28 Antigens / Q000096:biosynthesis*; D049109:Cell Proliferation; D002470:Cell Survival; D003713:Dendritic Cells / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020014:K562 Cells; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010950:Plasma Cells / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology
D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases