Dual Faces of IFNγ in Cancer Progression: A Role of PD-L1 Induction in the Determination of Pro- and Antitumor Immunity

IFNγ is a cytokine that plays a pivotal role in antitumor host immunity. IFNγ elicits potent antitumor immunity by inducing Th1 polarization, CTL activation, and dendritic cell tumoricidal activity. However, there are significant discrepancies in our understanding of the role of IFNγ as an antitumor cytokine. In certain circumstances, IFNγ obviously acts to induce tumor progression. IFNγ treatment has negatively affected patient outcomes in some clinical trials, while it has favorably affected outcomes in other trials. Several mechanisms, including IFNγ insensitivity and the downregulation of the MHC complex, have been regarded as the reasons for this discrepancy, but they do not fully explain it. We propose IFNγ-induced programmed cell death 1 ligand 1 (PD-L1) expression as a novel mechanism by which IFNγ impairs tumor immunity. When tumor cells encounter CTLs in the local environment, they detect them via the high concentration of IFNγ 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 IFNγ is thought to be a representative antitumor cytokine, it actually has dual roles: one as a hallmark of antitumor 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. Clin Cancer Res; 22(10); 2329-34. ©2016 AACR.