Deletion of the deISGylating enzyme USP18 enhances tumour cell antigenicity and radiosensitivity.

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., Kessler BM.

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.

DOI

10.1038/s41416-020-01167-y

Type

Journal article

Journal

Br J Cancer

Publication Date

02/2021

Volume

124

Pages

817 - 830

Keywords

Antigenic Variation, Cell Line, Tumor, Colorectal Neoplasms, Cytokines, Gene Knockout Techniques, HCT116 Cells, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Radiation Tolerance, Ubiquitin Thiolesterase, Ubiquitins

Permalink Original publication