IL-21 dampens NFkB activation to augment efficacy of CD8+ T cell mediated adoptive cell therapy (ACT)

Exploiting mechanisms integrating antigen and cytokine signals to generate tumor-antigen specific CD8+ T cells that are durable and produce low proinflammatory profile can boost efficacy of adoptive cell therapy (ACT) of cancer. Herein, we show that IL-21 via STAT3 induces the atypical IKK family member, Bcl3, to dampen antigen driven NF-kB (p65/p50) activation. The IL-21 induced Bcl3 decreases antigen driven CD8+ proliferation as well as apoptosis to increase clonal expansion. Strikingly, Bcl3 skews expression of master transcriptional factors to facilitate transition of polyfunctional CD8+ effector cells to memory precursor cells (MPCs) with cytotoxicity but reduced IFNg production. The IL-21 conditioned CD8+ T cells are persistent and produce greater tumor efficacy upon adoptive transfer. These studies have revealed a role for NF-kB to serve as a node for integrating antigen and cytokine signals that determine fate of antigen stimulated CD8+ T cells and encourage development of new approaches to target NFkB for T cell mediated immunity.