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

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.