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Prolonged IKKβ Inhibition Improves Ongoing CTL Antitumor Responses by Incapacitating Regulatory T Cells

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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, Vol. 21, No. 3, 17.10.2017, p. 578-586.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Heuser, C, Gotot, J, Piotrowski, EC, Philipp, M-S, Courrèges, CJF, Otte, MS, Guo, L, Schmid-Burgk, JL, Hornung, V, Heine, A, Knolle, PA, Garbi, N, Serfling, E, Evaristo, C, Thaiss, F & Kurts, C 2017, 'Prolonged IKKβ Inhibition Improves Ongoing CTL Antitumor Responses by Incapacitating Regulatory T Cells', CELL REP, vol. 21, no. 3, pp. 578-586. https://doi.org/10.1016/j.celrep.2017.09.082

APA

Heuser, C., Gotot, J., Piotrowski, E. C., Philipp, M-S., Courrèges, C. J. F., Otte, M. S., Guo, L., Schmid-Burgk, J. L., Hornung, V., Heine, A., Knolle, P. A., Garbi, N., Serfling, E., Evaristo, C., Thaiss, F., & Kurts, C. (2017). Prolonged IKKβ Inhibition Improves Ongoing CTL Antitumor Responses by Incapacitating Regulatory T Cells. CELL REP, 21(3), 578-586. https://doi.org/10.1016/j.celrep.2017.09.082

Vancouver

Heuser C, Gotot J, Piotrowski EC, Philipp M-S, Courrèges CJF, Otte MS et al. Prolonged IKKβ Inhibition Improves Ongoing CTL Antitumor Responses by Incapacitating Regulatory T Cells. CELL REP. 2017 Oct 17;21(3):578-586. https://doi.org/10.1016/j.celrep.2017.09.082

Bibtex

@article{b6068eeb4479461d9acb6a108df9bb4c,
title = "Prolonged IKKβ Inhibition Improves Ongoing CTL Antitumor Responses by Incapacitating Regulatory T Cells",
abstract = "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.",
keywords = "Animals, Cross-Priming, Homeostasis, I-kappa B Kinase, Lymphocyte Activation, Mice, NFATC Transcription Factors, Neoplasms, Phenotype, Signal Transduction, T-Lymphocytes, Cytotoxic, T-Lymphocytes, Regulatory, Vaccination, Journal Article",
author = "Christoph Heuser and Janine Gotot and Piotrowski, {Eveline Christina} and Marie-Sophie Philipp and Courr{\`e}ges, {Christina Johanna Felicia} and Otte, {Martin Sylvester} and Linlin Guo and Schmid-Burgk, {Jonathan Leo} and Veit Hornung and Annkristin Heine and Knolle, {Percy Alexander} and Natalio Garbi and Edgar Serfling and C{\'e}sar Evaristo and Friedrich Thaiss and Christian Kurts",
note = "Copyright {\textcopyright} 2017 The Author(s). Published by Elsevier Inc. All rights reserved.",
year = "2017",
month = oct,
day = "17",
doi = "10.1016/j.celrep.2017.09.082",
language = "English",
volume = "21",
pages = "578--586",
journal = "CELL REP",
issn = "2211-1247",
publisher = "Elsevier",
number = "3",

}

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 -