OntakTM blocks DC maturation by coreceptor downmodulation and inhibition of Stat3 phosphorylation to induce a tolerogenic phenotype
OntakTM kills activated CD4 T cells but stimulates anti-apoptosis in resting Treg by engagement and stimulation through CD25
Denileukin diftitox (DD), a diphtheria toxin fragment-IL-2 fusion-protein is thought to target and kill CD25+ cells. It is approved for the treatment of cutaneous T-cell lymphoma (CTCL) and used experimentally for the depletion of regulatory T cells (Treg) in cancer trials. Curiously enough, clinical effects of DD did not strictly correlate with CD25 expression and Treg depletion was not confirmed unambiguously. Here we report that melanoma patients receiving DD immediately prior to a dendritic cell (DC)-vaccine failed to develop a tumor-antigen-specific CD4 and CD8 T cell immune response even after repeated vaccinations. Analyzing the underlying mechanism, we found so far unknown effects of DD. First, DD modulated DC towards tolerance by down-regulating costimulatory-receptors like CD83 and CD25 while up-regulating tolerance-associated proteins/pathways including Stat-3, β-catenin and CIITA-dependent antigen presentation. Second, DD blocked Stat3 phosphorylation in maturing DC and third, only activated but not resting Treg internalized DD and were killed. Conversely, resting Treg showed increased survival due to DD-mediated anti-apoptotic IL-2 signaling. We conclude that DD exerts functions beyond CD25+ cell killing that may affect their clinical use and could be tested for novel indications. (Registered at: clinical trials.gov NCT00056134)
- Submitted September 25, 2012.
- Accepted July 23, 2013.
- Copyright © 2005 American Society of Hematology