Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion

Abstract

Interferon-gamma (IFN-γ) is a pleiotropic molecule with associated antiproliferative, pro-apoptotic and antitumor mechanisms. This effector cytokine, often considered as a major effector of immunity, has been used in the treatment of several diseases, despite its adverse effects. Although broad evidence implicating IFN-γ in tumor immune surveillance, IFN-γ-based therapies undergoing clinical trials have been of limited success. In fact, recent reports suggested that it may also play a protumorigenic role, namely, through IFN-γ signaling insensitivity, downregulation of major histocompatibility complexes, and upregulation of indoleamine 2,3-dioxygenase and of checkpoint inhibitors, as programmed cell-death ligand 1. However, the IFN-γ-mediated responses are still positively associated with patient's survival in several cancers. Consequently, major research efforts are required to understand the immune contexture in which IFN-γ induces its intricate and highly regulated effects in the tumor microenvironment. This review discusses the current knowledge on the pro- and antitumorigenic effects of IFN-γ as part of the complex immune response to cancer, highlighting the relevance to identify IFN-γ responsive patients for the improvement of therapies that exploit associated signaling pathways.

Keywords: cancer microenvironment; immune contexture; immunoregulation; immunotherapy; type II interferon.

Figure 1

Interferon-gamma (IFN-γ) canonical signaling pathway. Upon ligand binding, IFNγR1 and IFNγR2 oligomerize and transphosphorylate, activating Janus activated kinase (JAK) 1 and JAK2. These, in turn, phosphorylate IFNγR1, creating a docking site for the signal transducer and activator of transcription (STAT) 1. Phosphorylated STAT1 homodimerizes in an antiparallel configuration, forming a complex gamma-activated factor (GAF), which translocates to the nucleus and binds to gamma-activated site (GAS), located at the promoters of primary response genes, increasing their transcription. Upon induction, transcription factor interferon-regulatory factor 1 (IRF1) binds to interferon-stimulated response element (ISRE) and enhances the transcription of several secondary response genes responsible for several immunomodulatory functions. Suppressor of cytokine signaling (SOCS) proteins negatively regulate the IFN-γ pathway by inhibiting JAKs and STAT1 phosphorylation. Through dephosphorylation and deacetylation, the configuration of STAT1 homodimers reverts to parallel, triggering their exit from the nucleus.

Figure 2

Immunomodulatory effects of interferon-gamma (IFN-γ). IFN-γ produced by immune cells affects the behavior of distinct immune cells within the tumor microenvironment. Specifically, IFN-γ plays a major role in activating anticancer immunity, by promoting the activity of CD4 T helper type 1 cells, CD8 cytotoxic T lymphocyte (CTL), natural killer (NK) cells, dendritic cells (DCs), and macrophages, promoting the antigen presentation. Additionally, IFN-γ activates macrophages towards a more pro-inflammatory and tumoricidal phenotype (M1-like). Alternatively, IFN-γ inhibits regulatory T (Treg) cells, Th2 and Th17 differentiation and functions.

Figure 3

Dual face of interferon-gamma (IFN-γ) in tumor immunity. IFN-γ can display both antitumor and protumor activities. Under both circumstances, IFN-γ influences tumor cells directly and indirectly, by activation of immune cells. The antitumor effects comprise the development, recruitment, and activation of innate immune cells as well as the activation and maintenance of effector T cells. The antitumor effects of IFN-γ result in direct inhibition of tumor proliferation, recognition, and elimination. In other way, the protumorigenic role of IFN-γ involves proliferative and antiapoptotic signals, as well as escape of the tumor cells from recognition and cytolysis by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. The broad range of IFN-γ actions depends on the context of tumor specificity, IFN-γ-signaling intensity, and other microenvironment conditions.

Figure 4

Modulation of antigen-presenting cells (APCs) profile as anticancer therapeutic strategies. The tumor microenvironment is frequently immunosuppressive with APCs functions compromised, and consequently with poor T cell response. As APCs can be modulated by microenvironmental signals, these cells are promising targets. Interferon-gamma (IFN-γ) and other molecules can be used to re-educate tumor-associated macrophages, frequently associated with anti-inflammatory status (M2-like) toward a pro-inflammatory and antitumor profile, while stimulating regulatory dendritic cells (DCs) to an immunostimulatory profile. This stimulation can potentiate effector T cell response and inhibit tumor progression.