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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 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, suggesting 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 partially 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.

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Fig. 1: Induction of Ifng signaling enhances melanoma tumorigenesis.
Fig. 2: Ifng signaling enhances metastasis.
Fig. 3: Ifng-mediated enhancement of lung tumorigenesis is through Stat1 but not Stat3.
Fig. 4: Host immune response is necessary for the Ifng-mediated enhancement of melanoma lung colonization.
Fig. 5: Analyses of immune cell infiltration in the tumor microenvironment.
Fig. 6: Requirement for γδ T cells in Ifng-enhanced melanoma lung tumorigenesis.

Data availability

RNA-Seq data have been deposited in the Gene Expression Omnibus (GEO) and can be accessed through the accession number GSE214873.

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Funding

USA National Institutes of Health, R01CA193711 (MRZ); R01CA236391 (DJK), R01AI068907 (DJK), P30CA006927 (FCCC Comprehensive Cancer Center Core Grant).

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Contributions

BZ and JB: Conceptualization, methodology, investigation, data acquisition, and paper writing. HRK, XM, and SPA: methodology and data acquisition. KQC: Histopathological analyses and quantification. KNC: Bioinformatic analysis of RNA-Seq data. DJK: Investigation, acquisition of the grant, data interpretation, review and editing of paper. MRZ: Conceptualization, acquisition of grant, data interpretation, project supervision, and paper writing.

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Correspondence to M. Raza Zaidi.

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Zhou, B., Basu, J., Kazmi, H.R. et al. Interferon-gamma signaling promotes melanoma progression and metastasis. Oncogene 42, 351–363 (2023). https://doi.org/10.1038/s41388-022-02561-x

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