학술논문
Deletion of the deISGylating enzyme USP18 enhances tumour cell antigenicity and radiosensitivity
Document Type
Original Paper
Author
Pinto-Fernandez, Adan; Salio, Mariolina; Partridge, Tom; Chen, Jianzhou; Vere, George; Greenwood, Helene; Olie, Cyriel Sebastiaan; Damianou, Andreas; Scott, Hannah Claire; Pegg, Henry Jack; Chiarenza, Alessandra; Díaz-Saez, Laura; Smith, Paul; Gonzalez-Lopez, Claudia; Patel, Bhavisha; Anderton, Emma; Jones, Neil; Hammonds, Tim R.; Huber, Kilian; Muschel, Ruth; Borrow, Persephone; Cerundolo, Vincenzo; Kessler, Benedikt M.
Source
British Journal of Cancer. 124(4):817-830
Subject
Language
English
ISSN
0007-0920
1532-1827
1532-1827
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.