Universität zu Köln

Heuser, Christoph ORCID: 0000-0003-1410-7573, Gotot, Janine, Piotrowski, Eveline Christina, Philipp, Marie-Sophie, Courreges, Christina Johanna Felicia, Otte, Martin Sylvester, Guo, Linlin, Schmid-Burgk, Jonathan Leo, Hornung, Veit ORCID: 0000-0002-4150-194X, Heine, Annkristin, Knolle, Percy Alexander, Garbi, Natalio, Serfling, Edgar, Evaristo, Cesar, Thaiss, Friedrich and Kurts, Christian (2017). Prolonged IKK beta Inhibition Improves Ongoing CTL Antitumor Responses by Incapacitating Regulatory T Cells. Cell Reports, 21 (3). S. 578 - 587. CAMBRIDGE: CELL PRESS. ISSN 2211-1247

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Abstract

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 IKKb 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 similar to 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Heuser, Christoph UNSPECIFIED orcid.org/0000-0003-1410-7573 UNSPECIFIED Gotot, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Piotrowski, Eveline Christina UNSPECIFIED UNSPECIFIED UNSPECIFIED Philipp, Marie-Sophie UNSPECIFIED UNSPECIFIED UNSPECIFIED Courreges, Christina Johanna Felicia UNSPECIFIED UNSPECIFIED UNSPECIFIED Otte, Martin Sylvester UNSPECIFIED UNSPECIFIED UNSPECIFIED Guo, Linlin UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmid-Burgk, Jonathan Leo UNSPECIFIED UNSPECIFIED UNSPECIFIED Hornung, Veit UNSPECIFIED orcid.org/0000-0002-4150-194X UNSPECIFIED Heine, Annkristin UNSPECIFIED UNSPECIFIED UNSPECIFIED Knolle, Percy Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Garbi, Natalio UNSPECIFIED UNSPECIFIED UNSPECIFIED Serfling, Edgar UNSPECIFIED UNSPECIFIED UNSPECIFIED Evaristo, Cesar UNSPECIFIED UNSPECIFIED UNSPECIFIED Thaiss, Friedrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Kurts, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-214128
DOI:	10.1016/j.celrep.2017.09.082
Journal or Publication Title:	Cell Reports
Volume:	21
Number:	3
Page Range:	S. 578 - 587
Date:	2017
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	2211-1247
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NF-KAPPA-B; DENDRITIC CELLS; TRANSCRIPTION FACTOR; NUCLEAR-FACTOR; SURVIVAL; INFILTRATION; INFLAMMATION; HOMEOSTASIS; ACTIVATION; EXPRESSION Multiple languages Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21412