TNF-alpha-converting enzyme (TACE/ADAM17)-dependent loss of CD30 induced by proteasome inhibition through reactive
A M Vahdat1, K S Reiners, V L Simhadri
1Laboratory of Immunotherapy, Department I of Internal Medicine, University Clinic Cologne, Cologne 50924, Germany.
Abstract:
Combinations with proteasome inhibitors are currently being investigated to improve the therapy of hematological malignancies. We previously found that proteasome inhibition by bortezomib failed to sensitize anti-CD30 antibody (Ab)-based lymphoma cell killing. In this study, we demonstrate in L540 Hodgkin's lymphoma cells that proteasome inhibition not only communicates apoptosis but also more rapidly causes a loss of CD30 antigen from cell membrane and a simultaneous release of soluble CD30, a targeting competitor. This shedding was catalyzed by the tumor necrosis factor (TNF)-alpha-converting enzyme (TACE, ADAM17) and blocked by the ADAM17-selective inhibitor, Ro32-7315. In parallel with CD30 shedding, bortezomib caused the generation of reactive oxygen species (ROS). As apoptosis and shedding were inhibited by the radical scavenger, N-acetyl-L-cysteine, ROS might have a pivotal function in both effects. In contrast, the pan-caspase inhibitor, zVAD-fmk, blocked bortezomib-induced apoptosis but not CD30 shedding, and Ro32-7315 blocked shedding but allowed apoptosis. This suggests independent terminal signaling pathways that are conflicting in Ab-based immunotherapy. Consequently, shedding inhibition substantially improved the synergistic antitumor efficacy of the human anti-CD30 Ab, MDX-060, and bortezomib. As proteasome inhibition also stimulated loss of TNF receptors, interleukin-6 receptor and syndecan-1 in different leukemia and lymphoma cell lines, we concluded that proteasome inhibition might impede targeted therapy against antigens susceptible to shedding.
Insights
Proteasome inhibitors like bortezomib cause CD30 antigen shedding in lymphoma cells, hindering antibody therapy. Inhibiting this shedding enhances treatment efficacy against hematological malignancies.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Proteasome inhibitors are explored for hematological malignancy therapy.
- Bortezomib (proteasome inhibitor) previously failed to enhance anti-CD30 antibody lymphoma cell killing.
Purpose of the Study:
- Investigate bortezomib's effect on CD30 antigen expression and shedding in Hodgkin's lymphoma.
- Determine the role of reactive oxygen species (ROS) and ADAM17 in bortezomib-induced effects.
- Assess the impact of CD30 shedding on anti-CD30 antibody therapy efficacy.
Main Methods:
- Utilized L540 Hodgkin's lymphoma cells.
- Administered bortezomib, ADAM17 inhibitor (Ro32-7315), radical scavenger (N-acetyl-L-cysteine), and pan-caspase inhibitor (zVAD-fmk).
- Measured CD30 antigen expression, shedding, soluble CD30 release, ROS generation, and apoptosis.
Main Results:
- Bortezomib induced CD30 shedding and release of soluble CD30, mediated by ADAM17.
- Reactive oxygen species (ROS) were generated and implicated in both apoptosis and CD30 shedding.
- CD30 shedding and apoptosis followed independent signaling pathways.
- Inhibition of CD30 shedding improved the synergistic efficacy of anti-CD30 antibody (MDX-060) and bortezomib.
Conclusions:
- Proteasome inhibition can impede targeted antibody therapy by inducing antigen shedding.
- Bortezomib-induced CD30 shedding is an ADAM17-dependent process.
- Targeting antigen shedding may enhance the effectiveness of antibody-based immunotherapies in hematological cancers.
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