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Tumor B Cells From Non-Hodgkin's Lymphoma Are Resistant to CD95
(Fas/Apo-1)-Mediated Apoptosis
Joël Plumas,
Marie-Christine Jacob,
Laurence Chaperot,
Jean-Paul Molens,
Jean-Jacques Sotto, and
Jean-Claude Bensa
From the Immunology Department, ETS Isère-Savoie and Research
Group on Lymphoma, Unité UPRES 2021, Grenoble, France.
Apoptosis mediated by the CD95 (Fas/Apo-1) molecule plays a crucial
role in the regulation of the B-cell immune response. In this study, we
examined the function of the CD95 antigen in B-cell-derived
non-Hodgkin's lymphoma (NHL), a malignant disease of mature B cells.
Membrane CD95 molecules were found to be constitutively expressed in a
large number of NHL, including mantle cell (MCL, n = 10), lymphocytic
(LCL, n = 10), follicular (FL, n = 11), and diffuse large cell
lymphoma (DLCL, n = 9) with, however, different levels of intensity.
Indeed, the levels of CD95 were low in MCL and LCL as compared with FL
and DLCL. However, regardless of the intensity of expression, CD95
triggering with anti-CD95 monoclonal antibody (MoAb) did not induce
apoptosis of lymphoma B cells, while these cells underwent apoptosis
after irradiation or staurosporine treatment. Further experiments were
then performed to address whether apoptosis could be restored by B-cell
activation via CD40 cross-linking. We showed that CD40 engagement in
the presence of interleukin (IL)-4 was more effective than CD40
engagement alone in upregulating the CD95 antigen and induced
CD95-mediated cell death in nontumoral B cells. Concerning
malignant B cells, CD40 ligation in the presence of IL-4 strongly
increased CD95 expression, but did not markedly increase CD95-induced
apoptosis. Furthermore, using cytotoxic T cells, we showed that CD95L
was also ineffective in inducing apoptosis in lymphoma B cells, whereas these cells were killed by the perforin pathway. Our findings suggest
that the CD95-mediated cell death pathway is altered in malignant cells
from the NHL we tested. This could be a mechanism allowing lymphoma B
cells to escape from immune regulation.
Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 2875-2885
© 1998 by The American Society of Hematology.
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