Deletion of the deISGylating enzyme USP18 enhances tumour cell antigenicity and radiosensitivity
Adán Pinto-Fernández, Mariolina Salio, Tom Partridge, Jianzhou Chen, George Vere, Helene Greenwood, Cyriel Sebastiaan Olie, Andreas Damianou, Hannah C. Scott, Henry J. Pegg, Alessandra Chiarenza, L. Diaz Saez, Paul Smith, Claudia González-López, Bhavisha A. Patel, Emma Anderton, Neil P. Jones, Tim Hammonds, K. Huber, Ruth J. Muschel, Persephone Borrow, Vincenzo Cerundolo, Benedikt M. Kessler
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.