The group of Oncode Investigator Daniel Peeper (NKI) has published in Nature Communications its discovery of a new regulator of interferon γ (IFNγ) signaling. The IFNγ response pathway is associated with response to immunotherapy in cancer. The team found that high levels of the IFNγ-receptor (IFNγ-R1) affect the outcome of immunotherapy in a context-dependent fashion and identify the E3 ubiquitin ligase STUB1 as a negative regulator of IFNγ-R1/JAK1 expression in cancer cells.

The Peeper lab is interested in tackling mechanisms that limit the clinical benefit of immunotherapy, for example in the context of immune checkpoint blockade (ICB). One of the major signal transductions by which anticancer T cells combat cancer cells is the IFNγ pathway. Lead investigators Georgi Apriamashvili and David Vredevoogd, both PhD students in Peeper’s lab, noticed that although the IFNγ signaling pathway has been studied extensively, less is known about cell-intrinsic regulation of IFNγR1, its essential ligand-binding receptor chain residing at the tumor cell surface. Therefore, they made use of a favorite tool in the lab, function-based genome-wide CRISPR/Cas9 screens, to uncover critical factors regulating the abundance of IFNγ-R1 on tumor cells.

The investigators identified STUB1 as an E3 ubiquitin ligase for IFNγ-R1 in complex with its signal-relaying kinase JAK1. To crack the molecular mechanism, in collaboration with the group of Maarten Altelaar, they found that STUB1 mediates ubiquitination-dependent proteasomal degradation of IFNγ-R1/JAK1 complex through two residues, IFNγ-R1-K285 and JAK1-K249. Conversely, STUB1 inactivation amplifies IFNγ signaling, thereby sensitizing tumor cells to cytotoxic T cells in cell co-cultures.

Then, the PhD students set out to find any clinical correlates and found an anticorrelation between STUB1 expression and IFNγ response in patients treated with ICB. Lastly, they performed in vivo studies to determine any effect of STUB1 on the outcome of treatment. Apriamashvili and Vredevoogd found that the anti-PD-1 response is increased in heterogenous tumors comprising both wildtype and STUB1-deficient cells. They also noted that this was not seen for full STUB1 knockout tumors. Their results uncover STUB1 as a critical regulator of IFNγ-R1, but also highlight the context-dependency of STUB1-regulated IFNγ signaling for ICB outcome.

Peeper: “Georgi and David worked on this study for several years, because the signaling pathways triggered by IFNγ are not only controlled by complex intracellular mechanisms, but also affect T cell-mediated tumor killing in different ways. Other laboratories made similar observations, all pointing to the need for a better fundamental understanding of these events. Only then will we able to design more rational treatments aiming to improve the impact of immunotherapy”.

David Vredevoogd and Georgi Apriamashvili