TY  - JOUR
A1  - Heuser, Christoph
A1  - Gotot, Janine
A1  - Piotrowski, Eveline Christina
A1  - Philipp, Marie-Sophie
A1  - Courrèges, Christina Johanna Felicia
A1  - Otte, Martin Sylvester
A1  - Guo, Linlin
A1  - Schmid-Burgk, Jonathan Leo
A1  - Hornung, Veit
A1  - Heine, Annkristin
A1  - Knolle, Percy Alexander
A1  - Garbi, Natalio
A1  - Serfling, Edgar
A1  - Evaristo, César
A1  - Thaiss, Friedrich
A1  - Kurts, Christian
T1  - Prolonged IKK\(\beta\) Inhibition Improves Ongoing CTL Antitumor Responses by Incapacitating Regulatory T Cells
JF  - Cell Reports
N2  - 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 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.
KW  - medicine
KW  - regulatory T cells
KW  - NF-\(\kappa\)B pathway
KW  - tumor vaccination
KW  - checkpoint inhibition
KW  - cytotoxic T cells
KW  - cross-priming
KW  - apoptosis
KW  - tumor immunology
KW  - melanoma
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173643
VL  - 21
IS  - 3
ER  -