3 years ago

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

Prolonged IKKβ Inhibition Improves Ongoing CTL Antitumor Responses by Incapacitating Regulatory T Cells
César Evaristo, Christoph Heuser, Edgar Serfling, Natalio Garbi, Linlin Guo, Jonathan Leo Schmid-Burgk, Friedrich Thaiss, Janine Gotot, Annkristin Heine, Christina Johanna Felicia Courrèges, Percy Alexander Knolle, Eveline Christina Piotrowski, Christian Kurts, Veit Hornung, Martin Sylvester Otte, Marie-Sophie Philipp

Summary

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.

Publisher URL: http://www.cell.com/cell-reports/fulltext/S2211-1247(17)31387-6

DOI: 10.1016/j.celrep.2017.09.082

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