IFN-{gamma} and PD-L1 induction in cancer immunity

Interferon gamma (IFN-) is a cytokine that plays a pivotal role in antitumor host immunity. IFN- 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- as an antitumor cytokine. In certain circumstances, IFN- obviously acts to induce tumor progression. IFN- treatment has negatively affected patient outcomes in some clinical trials, while it has favorably affected outcomes in other trials. Several mechanisms, including IFN- 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--induced programmed cell death 1 ligand 1 (PD-L1) expression as a novel mechanism by which IFN- impairs tumor immunity. When tumor cells encounter CTLs in the local environment, they detect them via the high concentration of INF- 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- 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.

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