loxoribine and Precursor-B-Cell-Lymphoblastic-Leukemia-Lymphoma

Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy and, although current therapy is widely effective, relapse remains a significant clinical problem for which new treatment strategies are required. The ligation of Toll-like receptors (TLR) on antigen-presenting cells stimulates the generation of strong T-cell helper type 1 (Th1) adaptive immune responses. Although TLR9 ligation has been shown to enhance immunogenicity of a number of leukaemia cell types, there have been few reports of the effects mediated through other TLR. In this study we analysed both the expression of TLR by B-cell precursor ALL cell lines and the effects of individual TLR ligation on the ability of ALL cells to stimulate allogeneic T cells. While ligation of TLR2, TLR 7 and TLR9 led to detectable changes in ALL costimulatory molecule expression, only TLR2 and TLR9 stimulation influenced T-cell responses. The TLR2 ligand Pam3CysSerLys4 provoked the most significant changes in T-cell response, dramatically augmenting interferon-gamma production. These results suggest that TLR ligands, in addition to TLR9 agonists, may provide a strategy to enhance the generation of anti-ALL immune activity by skewing responding T cells towards a Th1 response.

Topics: CD40 Antigens; Cell Line, Tumor; Cell Proliferation; Guanosine; Humans; Immunotherapy; Interferon-gamma; Ligands; Peptidoglycan; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Protein Binding; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stimulation, Chemical; T-Lymphocytes, Helper-Inducer; Toll-Like Receptor 1; Toll-Like Receptor 2; Toll-Like Receptor 3; Toll-Like Receptor 4; Toll-Like Receptor 5; Toll-Like Receptor 7; Toll-Like Receptor 9; Toll-Like Receptors