Prolonged IKKβ Inhibition Improves Ongoing CTL Antitumor Responses by Incapacitating Regulatory T Cells
Standard
Prolonged IKKβ Inhibition Improves Ongoing CTL Antitumor Responses by Incapacitating Regulatory T Cells. / Heuser, Christoph; Gotot, Janine; Piotrowski, Eveline Christina; Philipp, Marie-Sophie; Courrèges, Christina Johanna Felicia; Otte, Martin Sylvester; Guo, Linlin; Schmid-Burgk, Jonathan Leo; Hornung, Veit; Heine, Annkristin; Knolle, Percy Alexander; Garbi, Natalio; Serfling, Edgar; Evaristo, César; Thaiss, Friedrich; Kurts, Christian.
in: CELL REP, Jahrgang 21, Nr. 3, 17.10.2017, S. 578-586.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Prolonged IKKβ Inhibition Improves Ongoing CTL Antitumor Responses by Incapacitating Regulatory T Cells
AU - Heuser, Christoph
AU - Gotot, Janine
AU - Piotrowski, Eveline Christina
AU - Philipp, Marie-Sophie
AU - Courrèges, Christina Johanna Felicia
AU - Otte, Martin Sylvester
AU - Guo, Linlin
AU - Schmid-Burgk, Jonathan Leo
AU - Hornung, Veit
AU - Heine, Annkristin
AU - Knolle, Percy Alexander
AU - Garbi, Natalio
AU - Serfling, Edgar
AU - Evaristo, César
AU - Thaiss, Friedrich
AU - Kurts, Christian
N1 - Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2017/10/17
Y1 - 2017/10/17
N2 - Regulatory T cells (Tregs) prevent autoimmunity but limit antitumor immunity. The canonical NF-κB signaling pathway both activates immunity and promotes thymic Treg development. Here, we report that mature Tregs continue to require NF-κB signaling through IκB-kinase β (IKKβ) after thymic egress. Mice lacking IKKβ in mature Tregs developed scurfy-like immunopathology due to death of peripheral FoxP3+ Tregs. Also, pharmacological IKKβ 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 IKKβ inhibition because other pathways, in particular nuclear factor of activated T cells (NFATc1) signaling, sustained their survival and expansion. In a melanoma mouse model, IKKβ inhibition after CTL cross-priming improved the antitumor response and delayed tumor growth. In conclusion, prolonged IKKβ inhibition decimates circulating Tregs and improves CTL responses when commenced after tumor vaccination, indicating that IKKβ represents a druggable checkpoint.
AB - Regulatory T cells (Tregs) prevent autoimmunity but limit antitumor immunity. The canonical NF-κB signaling pathway both activates immunity and promotes thymic Treg development. Here, we report that mature Tregs continue to require NF-κB signaling through IκB-kinase β (IKKβ) after thymic egress. Mice lacking IKKβ in mature Tregs developed scurfy-like immunopathology due to death of peripheral FoxP3+ Tregs. Also, pharmacological IKKβ 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 IKKβ inhibition because other pathways, in particular nuclear factor of activated T cells (NFATc1) signaling, sustained their survival and expansion. In a melanoma mouse model, IKKβ inhibition after CTL cross-priming improved the antitumor response and delayed tumor growth. In conclusion, prolonged IKKβ inhibition decimates circulating Tregs and improves CTL responses when commenced after tumor vaccination, indicating that IKKβ represents a druggable checkpoint.
KW - Animals
KW - Cross-Priming
KW - Homeostasis
KW - I-kappa B Kinase
KW - Lymphocyte Activation
KW - Mice
KW - NFATC Transcription Factors
KW - Neoplasms
KW - Phenotype
KW - Signal Transduction
KW - T-Lymphocytes, Cytotoxic
KW - T-Lymphocytes, Regulatory
KW - Vaccination
KW - Journal Article
U2 - 10.1016/j.celrep.2017.09.082
DO - 10.1016/j.celrep.2017.09.082
M3 - SCORING: Journal article
C2 - 29045828
VL - 21
SP - 578
EP - 586
JO - CELL REP
JF - CELL REP
SN - 2211-1247
IS - 3
ER -