Abstract
The cytokine IFNγ differentially impacts on tumors upon immune checkpoint blockade (ICB). Despite our understanding of downstream signaling events, less is known about regulation of its receptor (IFNγ-R1). With an unbiased genome-wide CRISPR/Cas9 screen for critical regulators of IFNγ-R1 cell surface abundance, we identify STUB1 as an E3 ubiquitin ligase for IFNγ-R1 in complex with its signal-relaying kinase JAK1. STUB1 mediates ubiquitination-dependent proteasomal degradation of IFNγ-R1/JAK1 complex through IFNγ-R1K285 and JAK1K249. Conversely, STUB1 inactivation amplifies IFNγ signaling, sensitizing tumor cells to cytotoxic T cells in vitro. This is corroborated by an anticorrelation between STUB1 expression and IFNγ response in ICB-treated patients. Consistent with the context-dependent effects of IFNγ 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 IFNγ-R1, and highlight the context-dependency of STUB1-regulated IFNγ signaling for ICB outcome.
| Original language | English |
|---|---|
| Article number | 1923 |
| Pages (from-to) | 1-16 |
| Journal | Nature Communications |
| Volume | 13 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 8 Apr 2022 |
Bibliographical note
Funding Information:We thank all members of the Peeper lab as well as of the Division of Molecular Oncology and Immunology for constructive feedback and valuable input. We thank R. Mezzadra, C. Sun, M. Toebes, T. Schumacher, J. Staring, T. Brummelkamp, A. Thouin and J. Jacobs for sharing reagents and cell lines. Furthermore, we thank the flow cytometry, proteomics and sequencing core facilities as well as the animal housing facility and the animal pathology department of The Netherlands Cancer Institute for their support. O.B.B and M.A. acknowledge support of the X-omics Initiative, part of the NWO National Roadmap for Large-Scale Research Infrastructures. J.D.L. was recipient of American Heart Grant 17POST33410945. J.C.S was recipient of National Institute on Aging Grant R01AG066710 and R01AG061188. D.S.P. is funded by the Oncode Institute, which is partly financed by the Dutch Cancer Society.
Funding Information:
We thank all members of the Peeper lab as well as of the Division of Molecular Oncology and Immunology for constructive feedback and valuable input. We thank R. Mezzadra, C. Sun, M. Toebes, T. Schumacher, J. Staring, T. Brummelkamp, A. Thouin and J. Jacobs for sharing reagents and cell lines. Furthermore, we thank the flow cytometry, proteomics and sequencing core facilities as well as the animal housing facility and the animal pathology department of The Netherlands Cancer Institute for their support. O.B.B and M.A. acknowledge support of the X-omics Initiative, part of the NWO National Roadmap for Large-Scale Research Infrastructures. J.D.L. was recipient of American Heart Grant 17POST33410945. J.C.S was recipient of National Institute on Aging Grant R01AG066710 and R01AG061188.?D.S.P.?is funded by?the Oncode Institute, which is partly financed by the Dutch Cancer Society.
Publisher Copyright:
© 2022, The Author(s).
Funding
We thank all members of the Peeper lab as well as of the Division of Molecular Oncology and Immunology for constructive feedback and valuable input. We thank R. Mezzadra, C. Sun, M. Toebes, T. Schumacher, J. Staring, T. Brummelkamp, A. Thouin and J. Jacobs for sharing reagents and cell lines. Furthermore, we thank the flow cytometry, proteomics and sequencing core facilities as well as the animal housing facility and the animal pathology department of The Netherlands Cancer Institute for their support. O.B.B and M.A. acknowledge support of the X-omics Initiative, part of the NWO National Roadmap for Large-Scale Research Infrastructures. J.D.L. was recipient of American Heart Grant 17POST33410945. J.C.S was recipient of National Institute on Aging Grant R01AG066710 and R01AG061188. D.S.P. is funded by the Oncode Institute, which is partly financed by the Dutch Cancer Society. We thank all members of the Peeper lab as well as of the Division of Molecular Oncology and Immunology for constructive feedback and valuable input. We thank R. Mezzadra, C. Sun, M. Toebes, T. Schumacher, J. Staring, T. Brummelkamp, A. Thouin and J. Jacobs for sharing reagents and cell lines. Furthermore, we thank the flow cytometry, proteomics and sequencing core facilities as well as the animal housing facility and the animal pathology department of The Netherlands Cancer Institute for their support. O.B.B and M.A. acknowledge support of the X-omics Initiative, part of the NWO National Roadmap for Large-Scale Research Infrastructures. J.D.L. was recipient of American Heart Grant 17POST33410945. J.C.S was recipient of National Institute on Aging Grant R01AG066710 and R01AG061188.?D.S.P.?is funded by?the Oncode Institute, which is partly financed by the Dutch Cancer Society.