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

Adán Pinto-Fernández ,Bhavisha Patel,Cyriel Sebastiaan Olie,Paul Smith,Hannah C Scott ,Vincenzo Cerundolo,Persephone Borrow,Mariolina Salio,Alessandra Chiarenza,L Diaz-Saez ,K Huber ,Helene Greenwood,Tim Hammonds ,Thomas Partridge ,Andreas Damianou,Neil P Jones ,Jianzhou Chen,Carlos G Lopez ,Henry J Pegg ,George Vere,Emma Anderton,Ruth J Muschel ,Benedikt M Kessler

doi:10.1038/s41416-020-01167-y

Abstract

BackgroundInterferon (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.MethodsIn 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.ResultsNovel 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.ConclusionsOur results provide strong evidence for USP18 in regulating antigenicity and radiosensitivity, highlighting its potential as a cancer target.

Highlights

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
In addition to the roles of elements of the innate immune response in modulating the efficacy of cancer immunotherapy, it has been reported that radiotherapy promotes the expression of interferon-stimulated genes (ISGs) that are involved in resistance to ionising irradiation.[10]
USP18 catalytic activity is essential for cell survival in the presence of type I IFN We decided to study the effects of type I interferon α 2 (IFNa2; IFN hereafter) on human HAP1 cells, a chronic myeloid leukaemia (CML)-derived cell line, in the presence or absence of the USP18 gene

Summary

Introduction

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. Numerous studies point towards defects in interferon-dependent pattern recognition pathways[3,4,5] and the antigen-presentation pathway[6,7] as the main resistance mechanisms tumour cells use to avoid the immune system and to escape the effects of immunotherapy.[8,9] In addition to the roles of elements of the innate immune response in modulating the efficacy of cancer immunotherapy, it has been reported that radiotherapy promotes the expression of interferon-stimulated genes (ISGs) that are involved in resistance to ionising irradiation.[10] Immunomodulatory imide drugs (IMiDs) such as thalidomide analogues are another category of immunomodulators that are routinely used to treat patients with multiple myeloma and lead to increased expression of ISGs.[11] there is strong evidence pointing at the innate immune response as a resistance mechanism that cancer cells use to survive the effects of immune checkpoint blockade and other cancer therapies

Methods

Results

Conclusion