The anti-metastatic effects of type 1 interferon (IFN1) prompted its use for adjuvant therapy in malignant melanoma patients at high risk for developing metastasis. While IFN1 adjuvant therapy continues to be the preferred treatment, many patients fail to elicit response to IFN1 treatment and progress to develop distal metastases often resulting in a lethal outcome. We observed downregulation of the IFNAR1 chain of the IFN1 receptor and suppression of IFN1 signaling in genetically engineered mouse melanomas driven by melanocyte-specific activation of Braf and inactivation of Pten. Induction of melanoma in animals expressing IFNAR1 that is deficient in ubiquitination and degradation led to a delayed onset of the disease and decreased number of local metastases. Remarkably, no distant metastases were found in these mice despite substantial primary tumor burden. Gene set enrichment analysis demonstrated a dramatic loss of the αv integrin pathway signature in mice harboring stabilized IFNAR1. Conversely, melanomas induced in Ifnar1 knockout mice yielded transplantable cell lines that displayed high levels of αv expression. Restoring IFNAR1 expression in these cells led to the loss of αv expression. We discuss the role of these mechanisms in melanoma metastasis and refractoriness to IFN1-based therapy.

Citation Format: Angelica Ortiz, Yuliya V. Katlinskaya, Kanstantsin V. Katlinski, Serge Y. Fuchs. IFNAR1 downregulation during melanoma progression upregulates αv expression and promotes metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A63.