The Dark Side of IFN-γ: Its Role in Promoting Cancer Immunoevasion

Abstract

Interferon-γ (IFN-γ) is a pleiotropic cytokine that has long been praised as an important effector molecule of anti-tumor immunity, capable of suppressing tumor growth through various mechanisms. On the contrary to such a bright side of IFN-γ, it has also been involved in promoting an outgrowth of tumor cells with immunoevasive phenotype suggesting an existence of a dark “tumor-promoting” side effect of IFN-γ. In this review, we will summarize this multi-functional role of IFN-γ in tumor context, how it promotes changes in tumor phenotype towards increased fitness for growth in immunocompetent host. Furthermore, we summarize how IFN-γ is involved in homeostatic or cancer-triggered mechanisms to establish an immunosuppressive tumor microenvironment.

Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development

“…In addition, higher levels of CD38 demarcates regulatory and memory status to CD8 + T cells in the context of IFNγ-mediated immunosuppression, and was recently addressed to drive mechanisms of tumour-mediated immune escape to immunotherapies using PD1/PD-L1 blockade [37,38]. Indeed, IFN-γ is upregulated in the context of BAP1 loss and is widely associated with several immune-suppressive network categories, which is in accordance with recent reports showing the immunesuppressive roles of IFN-γ [79].Therefore, targeting CD38 in UM may be considered a suitable strategy to improve the efficacy of immunotherapy using ICI in metastatic UM. A recent study showed that targeting CD38 using isatuximab can preferentially block immunosuppressive T-regulatory lymphocytes and therefore restore immune effector function against multiple myeloma [53].…”

The molecular landscape and microenvironment of salivary duct carcinoma reveal new therapeutic opportunities

“…An increase in interferon-γ (IFNG), a cytokine that can activate macrophages and NK cells, is also apparent. Interferon-γ adopts a pro-tumoral and immunosuppressive role in certain tumors (23) and, within the limits of the small cohort 1, a significant association of IFNG abundance with relapse was indeed observed (Suppl. Fig.…”

Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)

“…This results in a highly tolerogenic microenvironment characterized by reduced T effector lymphocytes and natural killer cells and an increased number of functionally active T regulatory cells and myeloid‐derived suppressor cells . The ratio between circulating kynurenine and tryptophan (KTR) can therefore be used as a surrogate of IDO activity and IFN‐γ‐mediated immune regulation in tumor microenvironment . IFN‐gamma also stimulates the production of neopterin, a metabolite of guanosine triphosphate, by macrophages .…”

“…11 The ratio between circulating kynurenine and tryptophan (KTR) can therefore be used as a surrogate of IDO activity and IFN-γ-mediated immune regulation in tumor microenvironment. 12 IFN-gamma also stimulates the production of neopterin, a metabolite of guanosine triphosphate, by macrophages. 13 One previous epidemiological study observed an association between KTR and higher risk of lung cancer.…”