1. Deletion of the deISGylating enzyme USP18 enhances tumour cell antigenicity and radiosensitivity.
- Author
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Pinto-Fernandez A, Salio M, Partridge T, Chen J, Vere G, Greenwood H, Olie CS, Damianou A, Scott HC, Pegg HJ, Chiarenza A, Díaz-Saez L, Smith P, Gonzalez-Lopez C, Patel B, Anderton E, Jones N, Hammonds TR, Huber K, Muschel R, Borrow P, Cerundolo V, and Kessler BM
- Subjects
- Antigenic Variation, Cell Line, Tumor, Colorectal Neoplasms radiotherapy, Gene Knockout Techniques, HCT116 Cells, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive radiotherapy, Radiation Tolerance genetics, Radiation Tolerance immunology, Ubiquitin Thiolesterase deficiency, Ubiquitin Thiolesterase genetics, Colorectal Neoplasms enzymology, Colorectal Neoplasms immunology, Cytokines metabolism, Leukemia, Myelogenous, Chronic, BCR-ABL Positive enzymology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive immunology, Ubiquitin Thiolesterase metabolism, Ubiquitins metabolism
- Abstract
Background: Interferon (IFN) signalling pathways, a key element of the innate immune response, contribute to resistance to conventional chemotherapy, radiotherapy, and immunotherapy, and are often deregulated in cancer. The deubiquitylating enzyme USP18 is a major negative regulator of the IFN signalling cascade and is the predominant human protease that cleaves ISG15, a ubiquitin-like protein tightly regulated in the context of innate immunity, from its modified substrate proteins in vivo., Methods: In this study, using advanced proteomic techniques, we have significantly expanded the USP18-dependent ISGylome and proteome in a chronic myeloid leukaemia (CML)-derived cell line. USP18-dependent effects were explored further in CML and colorectal carcinoma cellular models., Results: Novel ISGylation targets were characterised that modulate the sensing of innate ligands, antigen presentation and secretion of cytokines. Consequently, CML USP18-deficient cells are more antigenic, driving increased activation of cytotoxic T lymphocytes (CTLs) and are more susceptible to irradiation., Conclusions: Our results provide strong evidence for USP18 in regulating antigenicity and radiosensitivity, highlighting its potential as a cancer target.
- Published
- 2021
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