title: Denileukin diftitox (ONTAK) induces a tolerogenic phenotype in dendritic cells and stimulates survival of resting Treg.
abstract: 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 and is 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 patients with melanoma receiving DD immediately before 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, so far we found unknown effects of DD. First, DD modulated DCs toward tolerance by downregulating costimulatory receptors such as CD83 and CD25 while upregulating tolerance-associated proteins/pathways including Stat-3, β-catenin, and class II transactivator-dependent antigen presentation. Second, DD blocked Stat3 phosphorylation in maturing DCs. Third, only activated, but not resting, Treg internalized DD and were killed. Conversely, resting Treg showed increased survival because of DD-mediated antiapoptotic 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.
authors: Department of Dermatology, University Hospital Erlangen, Erlangen, Germany;
authors: Andreas S
authors: AS
authors: Baur
authors: Manfred B
authors: MB
authors: Lutz
authors: Stephan
authors: S
authors: Schierer
authors: Luca
authors: L
authors: Beltrame
authors: Gabi
authors: G
authors: Theiner
authors: Elisabeth
authors: E
authors: Zinser
authors: Christian
authors: C
authors: Ostalecki
authors: Gordon
authors: G
authors: Heidkamp
authors: Ina
authors: I
authors: Haendle
authors: Michael
authors: M
authors: Erdmann
authors: Manuel
authors: M
authors: Wiesinger
authors: Waltraud
authors: W
authors: Leisgang
authors: Stefanie
authors: S
authors: Gross
authors: Ansgar J
authors: AJ
authors: Pommer
authors: Eckhart
authors: E
authors: Kämpgen
authors: Diana
authors: D
authors: Dudziak
authors: Alexander
authors: A
authors: Steinkasserer
authors: Duccio
authors: D
authors: Cavalieri
authors: Beatrice
authors: B
authors: Schuler-Thurner
authors: Gerold
authors: G
authors: Schuler
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019496:Cancer Vaccines; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D004167:Diphtheria Toxin / Q000627:therapeutic use*; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000627:therapeutic use*; D007959:Lymphocyte Culture Test, Mixed; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D018613:Microscopy, Confocal; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000276:immunology / Q000628:therapy*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D004167:Diphtheria Toxin; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; C078456:denileukin diftitox