Interferon-γ-Mediated Inflammation: To Kill or Not to Kill

In the host immune system, cytotoxic T cells (CTLs) play a critical role in mounting an effective attack against tumorigenic cells. CTLs can drive this immunity through two mechanisms: direct lysis of tumor cells via cytolytic granule release and secretion of inflammatory cytokines such as interferon-γ (IFN-γ). While IFN-γ is well known for its role in upregulating major histocompatibility complex (MHC) class I presentation and differentiating naïve T cells into T helper 1 cells, its role in direct killing of tumor cells is less understood. In a recent study, we found that tumor cells lacking the signaling kinases TANK-binding kinase 1 (TBK1) and inhibitor of κB kinase ε (IKK-ε) were more easily killed by IFN-γ-producing T cells than their wild-type counterparts. In the absence of both kinases, IFN-γ upregulated the expression of both tumor necrosis factor receptor 1 (TNFR1) and the left-handed nuclei acid sensor Z-DNA-binding protein 1 (ZBP1) to trigger cell-autonomous apoptosis. Loss of TBK1 and IKK-ε also heightened nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation downstream of IFN-γ, along with increased production of inflammatory chemokines and cytokines. Thus, IFN-γ-induced death was paired with an inflammatory environment when the two kinases were absent. Our study illustrates that TBK1 and IKK-ε not only have a role in mediating a type I IFN response but also in regulating IFN-γ-induced death and NF-κB-dependent inflammation. Herein, we briefly highlight how the wiring of these kinases may have evolved over time to combat opportunistic pathogens and how this may shape our approach to cancer immunotherapy.