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

Cancer Immunol Immunother. 2010 Dec;59(12):1839-49. doi: 10.1007/s00262-010-0909-y. Epub 2010 Sep 4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, CD / physiology*
  • B7-H1 Antigen
  • Blast Crisis / immunology*
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic
  • Female
  • Humans
  • Interferon-gamma / physiology*
  • Intracellular Signaling Peptides and Proteins / physiology
  • Leukemia, Myeloid, Acute / pathology*
  • Male
  • Middle Aged
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Phosphatidylinositol 3-Kinases / physiology
  • Protein-Serine-Threonine Kinases / physiology
  • T-Lymphocytes, Cytotoxic / immunology*
  • TOR Serine-Threonine Kinases
  • Toll-Like Receptors / physiology*

Substances

  • Antigens, CD
  • B7-H1 Antigen
  • CD274 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Toll-Like Receptors
  • Interferon-gamma
  • Phosphatidylinositol 3-Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase Kinases