Interferon-gamma (IFN-γ) plays a crucial role in activating cellular immunity and subsequently stimulating anti-tumor immune responses. Due to its cell-inhibitory, pro-apoptotic, and anti-proliferative functions, IFN-γ is considered for adjunctive immunotherapy in various types of cancers. Additionally, IFN-γ can inhibit angiogenesis in tumor tissues, induce regulatory T cell apoptosis, and/or stimulate the activity of M1 pro-inflammatory macrophages to overcome tumor progression.
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Introduction of IFN-γ
Interferon-gamma (IFN-γ), discovered nearly 60 years ago, is a type II interferon encoded by the IFNG gene. Comprising two polypeptide chains, it undergoes glycosylation, enhancing its stability in the bloodstream. IFN-γ exhibits pleiotropic functions, influencing antiviral, antitumor, and immunomodulatory responses.
IFN-γ production is mainly regulated by natural killer (NK) and natural killer T (NKT) cells in innate immunity, while CD8+ and CD4+ T-cells are significant sources during adaptive immune responses. Stimulated by various factors, including interleukins and tumor-secreted antigens, IFN-γ production involves complex signaling pathways and transcription factors such as STAT4 and T-bet.
Fig. 1 Interferon-γ signaling (Jorgovanovic D., et al. 2020).
The IFN-γ Signaling pathways
The IFN-γ signaling pathways are intricate and vital in mediating various cellular responses. The canonical JAK-STAT pathway is initiated when IFN-γ binds to its receptor (IFNGR), composed of IFNGR1 and IFNGR2 subunits. This binding activates JAK1 and JAK2 kinases, leading to the phosphorylation and dimerization of STAT1 transcription factors. STAT1 homodimers then translocate to the nucleus, binding to the IFN-γ-activated site (GAS) and initiating the transcription of interferon signature genes (ISG), which regulate inflammatory signaling. The IFN-γ signaling pathway is negatively regulated by SHP phosphatases, SOCS1, SOCS3, and PIAS.
Moreover, alternative pathways activated by IFN-γ, distinct from the canonical ones, have been uncovered, highlighting the intricate nature of IFN-γ signaling. Varied concentrations of IFN-γ within the tumor microenvironment (TME) trigger specific pathways. Elevated concentrations activate the traditional JAK/STAT pathway, whereas lower concentrations initiate ICAM1-PI3K-Akt-Notch1 signaling, leading to heightened CD133 expression and the promotion of cancer stemness. The proposed crosstalk between JAK/STAT and PI3K-Akt pathways influences the expression of immune checkpoint ligands and other genes.
Moreover, IFN-γ has the capability to trigger the PI3K-Akt-mTOR pathway autonomously, separate from STAT signaling. This particular pathway is associated with the expression of CEACAM1 isoforms, fostering a positive feedback loop and prompting the release of inflammatory cytokines. The activation of the mTOR/p70S6 kinase cascade, pivotal for mRNA translation and protein synthesis, is induced by IFN-γ, indicating its role in facilitating IFN-γ-dependent biological effects.
The Roles of FN-γ in Cancer
IFN-γ plays a crucial role in cancer immunology, demonstrating dual effects on both anti-tumor and pro-tumor fronts. The anti-tumor mechanisms encompass the induction of apoptosis in cancer cells, augmentation of antigen-specific CD8+ T-cell activity, facilitation of tumor blood vessel destruction, inhibition of angiogenesis, and active contribution to an efficient anti-tumor immune response. Moreover, IFN-γ plays a supportive role in cancer immunotherapy by influencing the efficacy of immune checkpoint inhibitors, and its distinctive presence in gene expression profiles aligns with positive responses to these therapeutic interventions.
Additionally, IFN-γ has the potential to exert pro-tumor effects by fostering tumor metastasis, hindering T cell immune responses, triggering the expression of immune checkpoint receptors such as PD-L1 and IDO in tumors, and inciting cancer cell immunoediting. The concentration of IFN-γ in the tumor microenvironment (TME) assumes critical importance—lower doses may bolster tumor cell survival and metastatic capability, whereas higher doses can induce tumor regression. IFN-γ might induce the expression of PD-L1 and IDO in tumors, thereby impeding T-cell activity and facilitating immune escape.
Comprehending the delicate equilibrium of IFN-γ in cancer immunology is imperative for unlocking its potential as a potent anti-tumor molecule. Nevertheless, challenges emerge in harmonizing the dual roles of IFN-γ and tackling its tumor-promoting functions. The interplay between IFN-γ and other elements in the tumor microenvironment (TME), such as stromal cells, macrophages, and cytokines, adds layers of complexity to the scenario. Although IFN-γ holds promise in cancer therapy and immunotherapy, its intricate and context-dependent nature mandates continuous research for optimal clinical applications.
References
- Jorgovanovic D.; et al. Roles of IFN-γ in tumor progression and regression: a review. Biomarker Research. 2020, 8: 1-16.
- Zaidi M. R.; Merlino G. The two faces of interferon-γ in cancer. Clinical Cancer Research. 2011, 17(19): 6118-6124.
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