Nilotinib hampers the proliferation and function of CD8+ T lymphocytes through inhibition of T cell receptor signalling

J Cell Mol Med. 2008 Oct;12(5B):2107-18. doi: 10.1111/j.1582-4934.2008.00234.x. Epub 2008 Jan 11.

Abstract

The novel selective BCR-ABL Breakpoint cluster region--Abelson murine leukemia viral oncogene homolog 1 (BCR-AML) inhibitor nilotinib (AMN107) is a tyrosine kinase inhibitor that is more potent against leukaemia cells in vitro than imatinib. As nilotinib might be used in the context of allogeneic stem cell transplantation where CD8+ T lymphocytes play a pivotal role in the graft-versus-leukaemia (GVL) effect, we investigated effects of nilotinib on this lymphocyte subpopulation. Nilotinib inhibits phytohemagglutinin (PHA)-induced proliferation of CD8+T lymphocytes in vitro at therapeutically relevant concentrations (0.5-4 microM). The inhibition of CD8+ T lymphocytes specific for leukaemia or viral antigens through nilotinib was associated with a reduced expansion of antigen peptide specific CD8+ T lymphocytes and with a decreased release of interferon-gamma and granzyme B by these cells as analysed by flow cytometry and enzyme-linked immunospot (ELISPOT) assays. The inhibitory effect caused by nilotinib was two times stronger than by imatinib. These effects were mediated through the inhibition of the phosphorylation of ZAP-70, Lck and ERK 1/2 and the NF-kappaB signalling transduction pathway. Taken together, we observed a strong suppressive impact of nilotinib on the CD8+ T lymphocyte function which should be considered carefully in the framework of allogeneic stem cell transplantation or other T cell based immunotherapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • Case-Control Studies
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Pyrimidines / pharmacology*
  • Receptors, Antigen, T-Cell / drug effects*
  • Receptors, Antigen, T-Cell / immunology
  • Signal Transduction / drug effects*

Substances

  • 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
  • Antineoplastic Agents
  • Pyrimidines
  • Receptors, Antigen, T-Cell