Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-{gamma} and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway.
Multiple myeloma (MM) cells inhibit certain T-cell functions. We examined the expression of B7-H1 (PD-L1), a B7-related protein that inhibits T-cell responses, in CD138-purified plasma cells isolated from MM patients, monoclonal gammopathy of undetermined significance patients, and healthy donors. We observed that B7-H1 was expressed in most MM plasma cells, but not cells isolated from monoclonal gammopathy of undetermined significance or healthy donors. This expression was increased or induced by IFN-gamma and Toll-like receptor (TLR) ligands in isolated MM plasma cells. Blocking the MEK/ERK pathway inhibited IFN-gamma-mediated and TLR-mediated expression of B7-H1. Inhibition of the MyD88 and TRAF6 adaptor proteins of the TLR pathway blocked not only B7-H1 expression induced by TLR ligands but also that mediated by IFN-gamma. IFN-gamma-induced STAT1 activation, via MEK/ERK and MyD88/TRAF6, and inhibition of STAT1 reduced B7-H1 expression. MM plasma cells stimulated with IFN-gamma or TLR ligands inhibited cytotoxic T lymphocytes (CTLs) generation and this immunosuppressive effect was inhibited by preincubation with an anti-B7-H1 antibody, the UO126 MEK inhibitor, or by transfection of a dominant-negative mutant of MyD88. Thus, B7-H1 expression by MM cells represents a possible immune escape mechanism that could be targeted therapeutically through inhibition of MyD88/TRAF6 and MEK/ERK/STAT1.
Liu
Jizhong
J
Institut National de la Santé et de la Recherche Médicale, Unité 837, Institut de Recherche sur le Cancer de Lille, France.
Hamrouni
Abdelbasset
A
Wolowiec
Darius
D
Coiteux
Valérie
V
Kuliczkowski
Kazimierz
K
Hetuin
Dominique
D
Saudemont
Aurore
A
Quesnel
Bruno
B
D015703:Antigens, CD / Q000032:analysis* / Q000235:genetics; D060890:B7-H1 Antigen; D016022:Case-Control Studies; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008024:Ligands; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009101:Multiple Myeloma / Q000737:chemistry* / Q000473:pathology*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics; D010950:Plasma Cells / Q000737:chemistry / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000502:physiology*; D014407:Tumor Cells, Cultured; D019139:Tumor Escape / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D008024:Ligands; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D009363:Neoplasm Proteins; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D007371:Interferon-gamma; D020929:Mitogen-Activated Protein Kinase Kinases