Interferon-Gamma Signaling Promotes Melanoma Progression and Metastasis

Abstract

Interferon-gamma (IFNG) has long been regarded as the flag-bearer for the anti-cancer immunosurveillance mechanisms. However, relatively recent studies have suggested a dual role of IFNG, albeit there is no direct experimental evidence for its potential pro-tumor functions. Here we provide in vivo evidence that treatment of mouse melanoma cell lines with physiological levels of Ifng enhances their tumorigenicity and metastasis in lung colonization allograft assays performed in immunocompetent syngeneic host mice, but not in immunocompromised host mice. We also show that this enhancement is dependent on downstream signaling via Stat1 but not Stat3, providing evidence of an oncogenic function of Stat1 in melanoma. The experimental results suggest that melanoma cell-specific Ifng signaling modulates the tumor microenvironment and its pro-tumorigenic effects are dependent on the γδ T cells, as Ifng-enhanced tumorigenesis was inhibited in the TCR-δ knockout mice. Overall, these results show that Ifng signaling may have tumor-promoting effects in melanoma by modulating the immune cell composition of the tumor microenvironment.

Targeting inflamed and non-inflamed melanomas: biological background and clinical challenges

“…Despite the importance of IFNγ for tumor immunity, it has a pleiotropic role and can also contribute to melanoma progression and resistance to immunotherapy. Pre-clinical studies have demonstrated that IFNγ can enhance melanoma growth and metastases and inhibit tumor cell apoptosis by facilitating a protumoral microenvironment through the enrichment of immunosuppressive polymorphonuclear leukocytes (PMN) and TGFβ-producing γδ T cells [46]. In addition, its well described that IFNγ signaling induces the expression of immune checkpoint receptors, such as PD-L1, on tumor and immune cells [47][48][49].…”