Apriamashvili G, Vredevoogd DW, Krijgsman O, Bleijerveld OB, Ligtenberg MA, de Bruijn B, Boshuizen J, Traets JJH, D'Empaire Altimari D, van Vliet A, Lin CP, Visser NL, Londino JD, Sanchez-Hodge R, Oswalt LE, Altinok S, Schisler JC, Altelaar M, Peeper DS

The cytokine IFN? differentially impacts on tumors upon immune checkpoint blockade (ICB). Despite our understanding of downstream signaling events, less is known about regulation of its receptor (IFN?-R1). With an unbiased genome-wide CRISPR/Cas9 screen for critical regulators of IFN?-R1 cell surface abundance, we identify STUB1 as an E3 ubiquitin ligase ...

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for IFN?-R1 in complex with its signal-relaying kinase JAK1. STUB1 mediates ubiquitination-dependent proteasomal degradation of IFN?-R1/JAK1 complex through IFN?-R1K285 and JAK1K249. Conversely, STUB1 inactivation amplifies IFN? signaling, sensitizing tumor cells to cytotoxic T cells in vitro. This is corroborated by an anticorrelation between STUB1 expression and IFN? response in ICB-treated patients. Consistent with the context-dependent effects of IFN? in vivo, anti-PD-1 response is increased in heterogenous tumors comprising both wildtype and STUB1-deficient cells, but not full STUB1 knockout tumors. These results uncover STUB1 as a critical regulator of IFN?-R1, and highlight the context-dependency of STUB1-regulated IFN? signaling for ICB outcome.

Date: Apr. 08, 2022

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