Loss of optineurin drives cancer immune evasion via palmitoylation-dependent ifngr1 lysosomal sorting and degradation
dc.contributor.author | Du, W | |
dc.contributor.author | Hua, F | |
dc.contributor.author | Li, X | |
dc.contributor.author | Zhang, J | |
dc.contributor.author | Li, S | |
dc.contributor.author | Wang, W | |
dc.contributor.author | Zhou, J | |
dc.contributor.author | Wang, W | |
dc.contributor.author | Liao, P | |
dc.contributor.author | Yan, Y | |
dc.contributor.author | Li, G | |
dc.contributor.author | Wei, S | |
dc.contributor.author | Grove, S | |
dc.contributor.author | Vatan, L | |
dc.contributor.author | Zgodziński, W | |
dc.contributor.author | Majewski, M | |
dc.contributor.author | Wallner, G | |
dc.contributor.author | Chen, H | |
dc.contributor.author | Kryczek, I | |
dc.contributor.author | Fang, JY | |
dc.contributor.author | Zou, W | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2023-12-05T20:03:02Z | |
dc.date.available | 2023-12-05T20:03:02Z | |
dc.date.issued | 2021-07-01 | |
dc.identifier.issn | 2159-8274 | |
dc.identifier.issn | 2159-8290 | |
dc.identifier.uri | https://www.ncbi.nlm.nih.gov/pubmed/33627378 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/191680 | en |
dc.description.abstract | Mutations in IFN and MHC signaling genes endow immunotherapy resistance. Patients with colorectal cancer infrequently exhibit IFN and MHC signaling gene mutations and are generally resistant to immunotherapy. In exploring the integrity of IFN and MHC signaling in colorectal cancer, we found that optineurin was a shared node between the two pathways and predicted colorectal cancer patient outcome. Loss of optineurin occurs in early-stage human colorectal cancer. Immunologically, optineurin deficiency was shown to attenuate IFNGR1 and MHC-I expression, impair T-cell immunity, and diminish immunotherapy efficacy in murine cancer models and patients with cancer. Mechanistically, we observed that IFNGR1 was S-palmitoylated on Cys122, and AP3D1 bound with and sorted palmitoylated IFNGR1 to lysosome for degradation. Unexpectedly, optineurin interacted with AP3D1 to prevent palmitoylated IFNGR1 lysosomal sorting and degradation, thereby maintaining IFNγ and MHC-I signaling integrity. Furthermore, pharmacologically targeting IFNGR1 pal-mitoylation stabilized IFNGR1, augmented tumor immunity, and sensitized checkpoint therapy. Thus, loss of optineurin drives immune evasion and intrinsic immunotherapy resistance in colorectal cancer. Significance: Loss of optineurin impairs the integrity of both IFNγ and MHC-I signaling pathways via palmitoylation-dependent IFNGR1 lysosomal sorting and degradation, thereby driving immune evasion and intrinsic immunotherapy resistance in colorectal cancer. Our work suggests that pharmacologically targeting IFNGR1 palmitoylation can stabilize IFNGR1, enhance T-cell immunity, and sensitize checkpoint therapy in colorectal cancer. | |
dc.format.medium | Print-Electronic | |
dc.language | eng | |
dc.publisher | American Association for Cancer Research (AACR) | |
dc.subject | Animals | |
dc.subject | Cell Cycle Proteins | |
dc.subject | Colorectal Neoplasms | |
dc.subject | Female | |
dc.subject | Histocompatibility Antigens Class I | |
dc.subject | Humans | |
dc.subject | Interferon-gamma | |
dc.subject | Lipoylation | |
dc.subject | Male | |
dc.subject | Membrane Transport Proteins | |
dc.subject | Mice | |
dc.subject | Mice, Inbred C57BL | |
dc.subject | Mice, Inbred Strains | |
dc.subject | Protein Transport | |
dc.subject | Receptors, Interferon | |
dc.subject | Specific Pathogen-Free Organisms | |
dc.title | Loss of optineurin drives cancer immune evasion via palmitoylation-dependent ifngr1 lysosomal sorting and degradation | |
dc.type | Article | |
dc.identifier.pmid | 33627378 | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/191680/2/Loss of Optineurin Drives Cancer Immune Evasion via Palmitoylation-Dependent IFNGR1 Lysosomal Sorting and Degradation.pdf | |
dc.identifier.doi | 10.1158/2159-8290.CD-20-1571 | |
dc.identifier.doi | https://dx.doi.org/10.7302/21860 | |
dc.identifier.source | Cancer Discovery | |
dc.description.version | Published version | |
dc.date.updated | 2023-12-05T20:02:57Z | |
dc.identifier.orcid | 0000-0002-8409-5574 | |
dc.identifier.orcid | 0000-0002-2703-5268 | |
dc.identifier.orcid | 0000-0002-3130-2533 | |
dc.identifier.orcid | 0000-0001-7952-3549 | |
dc.description.filedescription | Description of Loss of Optineurin Drives Cancer Immune Evasion via Palmitoylation-Dependent IFNGR1 Lysosomal Sorting and Degradation.pdf : Published version | |
dc.identifier.volume | 11 | |
dc.identifier.issue | 7 | |
dc.identifier.startpage | 1826 | |
dc.identifier.endpage | 1843 | |
dc.identifier.name-orcid | Du, W | |
dc.identifier.name-orcid | Hua, F | |
dc.identifier.name-orcid | Li, X | |
dc.identifier.name-orcid | Zhang, J | |
dc.identifier.name-orcid | Li, S | |
dc.identifier.name-orcid | Wang, W | |
dc.identifier.name-orcid | Zhou, J | |
dc.identifier.name-orcid | Wang, W | |
dc.identifier.name-orcid | Liao, P; 0000-0002-8409-5574 | |
dc.identifier.name-orcid | Yan, Y | |
dc.identifier.name-orcid | Li, G | |
dc.identifier.name-orcid | Wei, S; 0000-0002-2703-5268 | |
dc.identifier.name-orcid | Grove, S | |
dc.identifier.name-orcid | Vatan, L | |
dc.identifier.name-orcid | Zgodziński, W | |
dc.identifier.name-orcid | Majewski, M | |
dc.identifier.name-orcid | Wallner, G | |
dc.identifier.name-orcid | Chen, H | |
dc.identifier.name-orcid | Kryczek, I; 0000-0002-3130-2533 | |
dc.identifier.name-orcid | Fang, JY | |
dc.identifier.name-orcid | Zou, W; 0000-0001-7952-3549 | |
dc.working.doi | 10.7302/21860 | en |
dc.owningcollname | Surgery, Department of |
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