The two faces of interferon-γ in cancer

Abstract

Interferon-γ is a cytokine whose biological activity is conventionally associated with cytostatic/cytotoxic and antitumor mechanisms during cell-mediated adaptive immune response. It has been used clinically to treat a variety of malignancies, albeit with mixed results and side effects that can be severe. Despite ample evidence implicating a role for IFN-γ in tumor immune surveillance, a steady flow of reports has suggested that it may also have protumorigenic effects under certain circumstances. We propose that, in fact, IFN-γ treatment is a double-edged sword whose anti- and protumorigenic activities are dependent on the cellular, microenvironmental, and/or molecular context. As such, inhibition of the IFN-γ/IFN-γ receptor pathway may prove to be a viable new therapeutic target for a subset of malignancies.

Figure 1

The canonical IFN-γ/JAK/STAT pathway. Binding of IFN-γ dimers to the extracellular domain of the IFNγR1 receptor subunit leads to engagement of the IFNγR2 subunit, which causes JAK1 and JAK2 to cross-phosphorylate each other and the receptor subunits. The parallel STAT1 homodimers are then recruited to the receptors, and their phosphorylation converts the homodimers into an antiparallel configuration. The reoriented STAT1 homodimers translocate to the nucleus, where they bind to gamma activated sequence (GAS) sites on the primary response genes including IRF1. IRF1 subsequently activates a large number of secondary response genes, which carry out a range of immunomodulatory functions. The SOCS proteins serve as the major negative regulators of the IFN-γ pathway by inhibiting the phosphorylation of JAKs and STAT1. Dephosphorylation and acetylation of STAT1 homodimers revert them to parallel configuration and causes their exit from the nucleus.

Figure 2

The two faces of IFN-γ. IFN-γ exhibits both anti-tumor and pro-tumor activities. Under both scenarios, IFN-γ influences the tumor cells directly as well as the development, recruitment and/or activation of immune response cells. The anti-tumor effects result in direct inhibition of tumor cell growth, and recognition and elimination of the tumor cells by the immune response cells. On the other hand, the pro-tumor functions of IFN-γ involve proliferative and anti-apoptotic signals, as well as escape of the tumor cells from recognition and cytolysis by CTLs and NK cells. Which face is ultimately displayed may depend on the contexts of tumor specificity, microenvironmental factors, and signaling intensity.