Nilotinib hampers the proliferation and function of CD8+ T lymphocytes through inhibition of T cell receptor signalling.
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.
Chen
J
J
Third Department of Internal Medicine, University of Ulm, Ulm, Germany.
Schmitt
A
A
Chen
B
B
Rojewski
M
M
Rübeler
V
V
Fei
F
F
Yu
Y
Y
Yu
X
X
Ringhoffer
M
M
von Harsdorf
S
S
Greiner
J
J
Götzz
M
M
Guillaume
P
P
Döhner
H
H
Bunjes
D
D
Schmitt
M
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D011743:Pyrimidines / Q000494:pharmacology*; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; D011743:Pyrimidines; D011948:Receptors, Antigen, T-Cell; C498826:nilotinib