Interferon γ and Its Important Roles in Promoting and Inhibiting Spontaneous and Therapeutic Cancer Immunity

Abstract

Originally identified in studies of cellular resistance to viral infection, interferon (IFN)-γ is now known to represent a distinct member of the IFN family and plays critical roles not only in orchestrating both innate and adaptive immune responses against viruses, bacteria, and tumors, but also in promoting pathologic inflammatory processes. IFN-γ production is largely restricted to T lymphocytes and natural killer (NK) cells and can ultimately lead to the generation of a polarized immune response composed of T helper (Th)1 CD4⁺ T cells and CD8⁺ cytolytic T cells. In contrast, the temporally distinct elaboration of IFN-γ in progressively growing tumors also promotes a state of adaptive resistance caused by the up-regulation of inhibitory molecules, such as programmed-death ligand 1 (PD-L1) on tumor cell targets, and additional host cells within the tumor microenvironment. This review focuses on the diverse positive and negative roles of IFN-γ in immune cell activation and differentiation leading to protective immune responses, as well as the paradoxical effects of IFN-γ within the tumor microenvironment that determine the ultimate fate of that tumor in a cancer-bearing individual.

Figure 1.

Assembly of the interferon (IFN)-γ receptor (IFNGR) and activation of Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling. Binding of IFN-γ to the IFNGR complex results in tight association of IFNGR1 and IFNGR2 and a reorientation of the intracellular domains of these subunits, thereby bringing their associated JAK1 and JAK2 proteins into close proximity to facilitate auto- and transphosphorylation and enzymatic activation. The activated JAK proteins then phosphorylate the intracellular domain of IFNGR1 on tyrosine 440 to create a binding site for STAT1. On JAK-mediated phosphorylation, STAT1 dissociates from its IFNGR1 tether, forms a homodimer via reciprocal interactions between the SH2 domain of one STAT1 molecule and the phosphorylated tyrosine-701 of the other, and translocates to the nucleus where it binds to γ-activated site (GAS) elements and promotes gene transcription. The multiple levels of JAK-STAT pathway negative regulation are indicated. SOCS, Suppressors of cytokine signaling; PIAS, protein inhibitor of activated STATs. (From Bach et al. 1997; adapted, with permission, from the authors.)

Figure 2.

Interferon (IFN)-γ influences all stages of tumor immunoediting. Tumor immunoediting involves three stages: (1) elimination, in which the immune system recognizes and destroys tumor cells expressing strong neoantigens; (2) equilibrium, in which the immune system controls the outgrowth of remaining immunogenic tumor cells by manifesting in them a state of immune-mediated dormancy; and (3) escape, in which the immune system can no longer control the outgrowth of edited tumor cells resulting in the progressive outgrowth of clinically apparent tumors and the establishment of an immunosuppressive tumor microenvironment. The roles played by IFN-γ are highlighted, with green arrows indicating its immune-stimulatory roles and red arrows indicating its immune-suppressive roles. NKT, Natural killer T cells; NK, natural killer; MHC, major histocompatibility complex; DC, dendritic cell; PD-L1, programmed-death ligand 1. (From Vesely et al. 2011; adapted, with permission, from the authors.)