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The two faces of CD40 stimulation in CLL Induction of apoptotic resistance and increased sensitivity of T-cell mediated killing


, : The two faces of CD40 stimulation in CLL Induction of apoptotic resistance and increased sensitivity of T-cell mediated killing. Blood 102(11): 434a, November 16

Introduction: B cell chronic lymphocytic leukemia (B-CLL) is a malignancy involving deregulated apoptosis. The extent to which various apoptotic pathways are still operative and can respond to regulatory signals is uncertain. Especially CD40-CD40L interactions are under investigation for therapeutic application in various immunomodulatory settings. CLL cells respond to CD40 triggering but the influence on the dysregulated apoptosis pathways is still unknown. Aim of the study: To investigate the influence of CD40 triggering of CLL cells on the expression of direct regulators of apoptosis and to correlate these findings with the sensitivity of CD40 triggered CLL cells for chemotherapy induced- and death-receptor induced apoptosis as well as T-cell mediated killing. Results: In order to comprehensively quantify gene expression of virtually all direct regulators (34 genes) of apoptosis, we implemented a novel reverse transcriptase multiplex ligation-dependent probe amplification assay (RT-MLPA). CLL cells displayed a high constitutive expression of Bcl-2 and Flip. After 3 days of coculture with CD40L transfected fibroblasts, the anti apoptotic profile was further increased by upregulation of BCL-xL, A1 and downregulation of the BH3-only protein Harakiri. CD40 stimulated CLL cells became resistant for fludarabine mediated apoptosis and despite up regulation of the FAS receptor, CD40 triggering did not lead to enhanced sensitivity of FAS and TRAIL. Remarkebly, autologous T-cell mediated killing was approximately 8 times more efficient after CD40 stimulation, with a 50% specific lysis at an effector:target (E:T) ratio of 1:1, in CD40 triggered, viral peptide loaded CLL cells. This killing was completely granzym B dependent. Conclusions: This first extensive gene expression profile of the influence of CD40 triggering on direct regulators of apoptosis in CLL cells revealed only 3 anti-apoptotic proteins to be influenced by CD40 stimulation. Although resulting in resistance to chemotherapy- and death receptor induced apoptosis, CD40 stimulation leads to increased sensitivity to T-cell mediated killing mediated by granzym B. We conclude that CD40 triggered CLL cells can be excellent targets of T-cell mediated killing despite an increased anti apoptotic profile.

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