Prolonged IKK? Inhibition Improves Ongoing CTL Antitumor Responses by Incapacitating Regulatory T Cells.

Regulatory T cells (Tregs) prevent autoimmunity but limit antitumor immunity. The canonical NF-?B signaling pathway both activates immunity and promotes thymic Treg development. Here, we report that mature Tregs continue to require NF-?B signaling through I?B-kinase ? (IKK?) after thymic egress. Mice lacking IKK? in mature Tregs developed scurfy-like immunopathology due to death of peripheral FoxP3 Tregs. Also, pharmacological IKK? 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 IKK? 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? inhibition after CTL cross-priming improved the antitumor response and delayed tumor growth. In conclusion, prolonged IKK? inhibition decimates circulating Tregs and improves CTL responses when commenced after tumor vaccination, indicating that IKK? represents a druggable checkpoint.     «

Regulatory T cells (Tregs) prevent autoimmunity but limit antitumor immunity. The canonical NF-?B signaling pathway both activates immunity and promotes thymic Treg development. Here, we report that mature Tregs continue to require NF-?B signaling through I?B-kinase ? (IKK?) after thymic egress. Mice lacking IKK? in mature Tregs developed scurfy-like immunopathology due to death of peripheral FoxP3 Tregs. Also, pharmacological IKK? inhibition reduced Treg numbers in the circulation by ~50% and d...     »