title: In acute myeloid leukemia, B7-H1 (PD-L1) protection of blasts from cytotoxic T cells is induced by TLR ligands and interferon-gamma and can be reversed using MEK inhibitors.
abstract: B7-H1 (PD-L1) is a B7-related protein that inhibits T-cell responses. B7-H1 participates in the immunoescape of cancer cells and is also involved in the long-term persistence of leukemic cells in a mouse model of leukemia. B7-H1 can be constitutively expressed by cancer cells, but is also induced by various stimuli. Therefore, we examined the constitutive and inducible expression of B7-H1 and the consequences of this expression in human acute myeloid leukemia (AML). We analyzed B7-H1 expression in a cohort of 79 patients with AML. In addition, we studied blast cells after incubation with interferon-gamma or toll-like receptors (TLR) ligands. Finally, we evaluated functionality of cytotoxic T-cell activity against blast cells. Expression of B7-H1 upon diagnosis was high in 18% of patients. Expression of TLR2, 4 and 9 was detected in one-third of AML samples. Expression of TLR2 and TLR4 ligands or IFN-γ induced by B7-H1 was found to protect AML cells from CTL-mediated lysis. Spontaneous B7-H1 expression was also found to be enhanced upon relapse in some patients. MEK inhibitors, including UO126 and AZD6244, reduced B7-H1 expression and restored CTL-mediated lysis of blast cells. In AML, B7-H1 expression by blasts represents a possible immune escape mechanism. The inducibility of B7-H1 expression by IFN-γ or TLR ligands suggests that various stimuli, either produced during the immune response against leukemia cells or released by infectious microorganisms, could protect leukemic cells from T cells. The efficacy of MEK inhibitors against B7-H1-mediated inhibition of CTLs suggests a possible cancer immunotherapy strategy using targeted drugs.
authors.affiliation: INSERM, unit 837, Institut de Recherche sur le Cancer de Lille, Lille, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Berthon
authors.forename: Virginie
authors.initials: V
authors.lastname: Driss
authors.forename: Jizhong
authors.initials: J
authors.lastname: Liu
authors.forename: Klaudia
authors.initials: K
authors.lastname: Kuranda
authors.forename: Xavier
authors.initials: X
authors.lastname: Leleu
authors.forename: Nathalie
authors.initials: N
authors.lastname: Jouy
authors.forename: Dominique
authors.initials: D
authors.lastname: Hetuin
authors.forename: Bruno
authors.initials: B
authors.lastname: Quesnel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000502:physiology*; D060890:B7-H1 Antigen; D001752:Blast Crisis / Q000276:immunology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases; D051193:Toll-Like Receptors / Q000502:physiology*
chemical_list: D015703:Antigens, CD; D060890:B7-H1 Antigen; D007371:Interferon-gamma; D047908:Intracellular Signaling Peptides and Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D051193:Toll-Like Receptors; C423236:CD274 protein, human; C546842:MTOR protein, human; C546843:mTOR protein, mouse
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