Interferon gamma in cancer immunotherapy

Abstract

Immune system can recognize self vs transformed self. That is why cancer immunotherapy achieves notable benefits in a wide variety of cancers. Recently, several papers reported that immune checkpoint blockade therapy led to upregulation of IFNγ and in turn clearance of tumor cells. In this review, we conducted an extensive literature search of recent 5-year studies about the roles of IFNγ signaling in both tumor immune surveillance and immune evasion. In addition to well-known functions, IFNγ signaling also induces tumor ischemia and homeostasis program, resulting in tumor clearance and tumor escape, respectively. The yin and the yang of IFNγ signaling are summarized. Thus, this review helps us to comprehensively understand the roles of IFNγ in tumor immunity, which contributes to better design and management of clinical immunotherapy approaches.

Keywords: IFNγ signaling; cancer immunotherapy; immune evasion; immune surveillance; transformed self.

Figure 1

The roles of IFNγ signaling in tumor clearance. IFNγ signaling activates STAT1. Phosphorylated STAT1 binds to specific promoter elements and modulate transcription of IFNγ‐regulated genes. The positive consequences of IFNγ ligation consist of increased efficacy of radiotherapy, induction of tumor cell apoptosis and necroptosis, generation of ischemia, activation of APCs, promotion of Treg cell fragility, inhibition of gMDSC function and switch M2 from TAMs

Figure 2

The roles of IFNγ signaling in tumor escape. IFNγ signaling induces tumor cells to express tolerant molecules, such as PD‐L1, which functions as a molecular shield to protect PD‐L1⁺ tumor cells from immune attack, while downregulates TNFSF15 to promote angiogenesis. In addition, IFNγ signaling induces Muc16 expression and homeostasis program to promote tumor progression

Figure 3

The yin and the yang of IFNγ signaling in cancer immunity. IFNγ plays a dual and opposing role in cancer development. IFNγ signaling inhibits tumor growth by arrest of tumor cell cycle, induction of tumor ischemia and activation of APCs and effector cells while impairing suppressive immune cells. Meantime, IFNγ contributes to tumor growth via promotion of tumorigenesis and angiogenesis, upregulation of tolerant molecules and induction of homeostasis program