CD40 stimulation of B-cell chronic lymphocytic leukaemia cells enhances the anti-apoptotic profile, but also Bid expression and cells remain susceptible to autologous cytotoxic T-lymphocyte attack.
To enhance the poor antigen-presenting capacity of B-cell chronic lymphocytic leukaemia (B-CLL), CD40 triggering has been considered as an active immunotherapy. However, CD40 stimulation also has an anti-apoptotic effect and may further impair the dysregulated response of B-CLL to apoptotic stimuli. Therefore, we measured the expression of virtually all regulators of apoptosis before and after CD40 stimulation. These findings were correlated with sensitivity for chemotherapy- and death-receptor-induced apoptosis and T-cell-mediated killing. CD40 stimulation enhanced the constitutive anti-apoptotic profile of B-CLL cells by upregulation of Bcl-xL and Bfl-1 and downregulation of the BH3-only protein Harakiri. Unexpectedly, the BH3-only protein Bid was strongly induced. Functionally, CD40-stimulated B-CLL cells became resistant to drug-induced apoptosis and, despite upregulation of CD95 and Bid, were not sensitive to CD95L. In contrast, autologous T cell killing, triggered by loading CLL cells with viral (CMV) peptides, was very efficient both before and after CD40 stimulation. Upon CTL interaction, CLL targets underwent mitochondrial depolarization and caspase-3 activation. Thus, despite an increased anti-apoptotic profile, CD40 triggered B-CLL cells remain excellent targets for resident cytotoxic T cells. These data support therapeutic exploitation of CD40 stimulation in B-CLL, provided that a strong CTL component is induced.
Kater
Arnon P
AP
Department of Haematology, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Evers
Ludo M
LM
Remmerswaal
Ester B M
EB
Jaspers
Annelieke
A
Oosterwijk
Michiel F
MF
van Lier
René A W
RA
van Oers
Marinus H J
MH
Eldering
Eric
E
D017209:Apoptosis / Q000276:immunology*; D051023:BH3 Interacting Domain Death Agonist Protein; D015153:Blotting, Western; D019013:CD40 Antigens / Q000276:immunology*; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003587:Cytomegalovirus / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D019014:fas Receptor / Q000276:immunology
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D019013:CD40 Antigens; D002352:Carrier Proteins; D019014:fas Receptor; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases