Prolonged IKK\(\beta\) Inhibition Improves Ongoing CTL Antitumor Responses by Incapacitating Regulatory T Cells
Zitieren Sie bitte immer diese URN: urn:nbn:de:bvb:20-opus-173643
- Regulatory T cells (Tregs) prevent autoimmunity but limit antitumor immunity. The canonical NF-\(\kappa\)B signaling pathway both activates immunity and promotes thymic Treg development. Here, we report that mature Tregs continue to require NF-\(\kappa\)B signaling through I\(\kappa\)B-kinase \(\beta\) (IKK\(\beta\)) after thymic egress. Mice lacking IKK\(\beta\) in mature Tregs developed scurfy-like immunopathology due to death of peripheral FoxP3\(^+\) Tregs. Also, pharmacological IKK\(\beta\) inhibition reduced Treg numbers in theRegulatory T cells (Tregs) prevent autoimmunity but limit antitumor immunity. The canonical NF-\(\kappa\)B signaling pathway both activates immunity and promotes thymic Treg development. Here, we report that mature Tregs continue to require NF-\(\kappa\)B signaling through I\(\kappa\)B-kinase \(\beta\) (IKK\(\beta\)) after thymic egress. Mice lacking IKK\(\beta\) in mature Tregs developed scurfy-like immunopathology due to death of peripheral FoxP3\(^+\) Tregs. Also, pharmacological IKK\(\beta\) inhibition reduced Treg numbers in the circulation by ~50% and downregulated FoxP3 and CD25 expression and STAT5 phosphorylation. In contrast, activated cytotoxic T lymphocytes (CTLs) were resistant to IKK\(\beta\) inhibition because other pathways, in particular nuclear factor of activated T cells (NFATc1) signaling, sustained their survival and expansion. In a melanoma mouse model, IKK\(\beta\) inhibition after CTL cross-priming improved the antitumor response and delayed tumor growth. In conclusion, prolonged IKK\(\beta\) inhibition decimates circulating Tregs and improves CTL responses when commenced after tumor vaccination, indicating that IKK\(\beta\) represents a druggable checkpoint.…
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| Autor(en): | Christoph Heuser, Janine Gotot, Eveline Christina Piotrowski, Marie-Sophie Philipp, Christina Johanna Felicia Courrèges, Martin Sylvester Otte, Linlin Guo, Jonathan Leo Schmid-Burgk, Veit Hornung, Annkristin Heine, Percy Alexander Knolle, Natalio Garbi, Edgar Serfling, César Evaristo, Friedrich Thaiss, Christian Kurts |
|---|---|
| URN: | urn:nbn:de:bvb:20-opus-173643 |
| Dokumentart: | Artikel / Aufsatz in einer Zeitschrift |
| Institute der Universität: | Medizinische Fakultät / Pathologisches Institut |
| Sprache der Veröffentlichung: | Englisch |
| Titel des übergeordneten Werkes / der Zeitschrift (Englisch): | Cell Reports |
| Erscheinungsjahr: | 2017 |
| Band / Jahrgang: | 21 |
| Heft / Ausgabe: | 3 |
| Seitenangabe: | 578-586 |
| Originalveröffentlichung / Quelle: | Cell Reports (2017) 21:3, pp. 578-586. https://doi.org/10.1016/j.celrep.2017.09.082 |
| DOI: | https://doi.org/10.1016/j.celrep.2017.09.082 |
| PubMed-ID: | https://pubmed.ncbi.nlm.nih.gov/29045828 |
| Allgemeine fachliche Zuordnung (DDC-Klassifikation): | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
| Freie Schlagwort(e): | NF-\(\kappa\)B pathway; apoptosis; checkpoint inhibition; cross-priming; cytotoxic T cells; medicine; melanoma; regulatory T cells; tumor immunology; tumor vaccination |
| Datum der Freischaltung: | 31.03.2022 |
| EU-Projektnummer / Contract (GA) number: | 668036 |
| OpenAIRE: | OpenAIRE |
| Lizenz (Deutsch): |  CC BY-NC-ND: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell, Keine Bearbeitungen 4.0 International |