1. Deletion of the deISGylating enzyme USP18 enhances tumour cell antigenicity and radiosensitivity
- Author
-
Henry Jack Pegg, Kilian Huber, Claudia Gonzalez-Lopez, Benedikt M. Kessler, Helene Greenwood, Adan Pinto-Fernandez, Jianzhou Chen, Persephone Borrow, Paul Smith, Mariolina Salio, Vincenzo Cerundolo, Cyriel S. Olie, Ruth J. Muschel, Alessandra Chiarenza, Andreas Damianou, L. Diaz-Saez, Tom Partridge, Neil P. Jones, Tim Hammonds, Hannah C. Scott, George Vere, Bhavisha Patel, and Emma Anderton
- Subjects
Cancer Research ,Antigenicity ,Ubiquitylation ,medicine.medical_treatment ,Antigen presentation ,Cancer immunotherapy ,Biology ,Radiation Tolerance ,Article ,Gene Knockout Techniques ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Interferon ,Cell Line, Tumor ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Humans ,Cytotoxic T cell ,Ubiquitins ,Innate immune system ,Radiotherapy ,Immunotherapy ,HCT116 Cells ,Antigenic Variation ,ISG15 ,Mechanisms of disease ,Oncology ,030220 oncology & carcinogenesis ,RIG-I-like receptors ,Cancer research ,Cytokines ,Colorectal Neoplasms ,Ubiquitin Thiolesterase ,medicine.drug - 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
- 2020