IFN

Interferon gamma (IFN-gamma) is a cytokine that plays a pivotal role in antitumor host immunity. IFN-gamma elicits potent antitumor immunity by inducing Th1 polarization, cytotoxic T lymphocyte (CTL) activation and dendritic cell tumoricidal activity. However, there are significant discrepancies in our understanding of the role of IFN-gamma as an antitumor cytokine. In certain circumstances, IFN-gamma obviously acts to induce tumor progression. IFN-gamma treatment has negatively affected patient outcomes in some clinical trials, while it has favorably affected outcomes in other trials. Several mechanisms, including IFN-gamma insensitivity and the downregulation of the major histocompatibility complex, have been regarded as the reasons for this discrepancy, but they do not fully explain it. We propose IFN-gamma-induced programmed cell death 1 ligand 1 (PD-L1) expression as a novel mechanism by which IFN-gamma impairs tumor immunity. When tumor cells encounter CTLs in the local environment, they detect them via the high concentration of INF-gamma secreted from CTLs, which induces PD-L1 expression in preparation for an immune attack. Thus, tumor cells acquire the capability to counterattack immune cells. These findings indicate that, although INF-gamma is thought to be a representative anti-tumor cytokine, it actually has dual roles: one as a hallmark of anti-tumor immunity and the other as an inducer of the immune escape phenomenon through various mechanisms, such as PD-L1 expression. In this context, the optimization of immunotherapy according to the local immune environment is important. Anti-PD-1/PD-L1 treatment may be particularly promising when efficient tumor immunity is present, but it is disturbed by PD-L1 expression.