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Mécanismes d'immunoévasion dans les leucémies aiguës myéloïdes : la molécules B7-H1

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. B7-H1 can be constitutively expressed by cancer cells but is also induced by various stimuli. We therefore examined the constitutive and inducible expression of B7-H1 and the consequences of expression in human acute myeloid leukemia (AML). We analyzed B7-H1 expression in a cohort of 79 patients with AML. Blast cells were also studied after incubation with interferon-gamma or TLR ligands. Functionality was evaluated by cytotoxic T-cell activity against blast cells. Expression of B7-H1 at diagnosis was high in 18% of patients. Expression of toll-like receptors (TLR) 2, 4, and 9 was detected in one-third of AML samples. Expression of TLR2 and TLR4 ligands or IFN- induced by B7-H1 was found to protect AML cells from CTL-mediated lysis. Spontaneous B7-H1 expression was also found to be enhanced at 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- 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.
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Céline Berthon. Mécanismes d'immunoévasion dans les leucémies aiguës myéloïdes : la molécules B7-H1. Médecine humaine et pathologie. Université du Droit et de la Santé - Lille II, 2012. Français. ⟨NNT : 2012LIL2S016⟩. ⟨tel-00787736⟩

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