Abstract LB-080: USP18 modulates the ISGylome, immune signaling and sensitizes tumor cells to irradiation and CTL recognition

Abstract

Abstract The innate immune response plays a critical role in modulating the efficacy of and mechanisms conferring resistance to immune checkpoint blockade (ICB) therapies in humans. A major negative regulator of the Interferon (IFN) stimulated gene (ISG) pathway, is the ubiquitin-specific protease 18 (USP18). USP18 is the predominant human deubiquitylating enzyme that processes Interferon Stimulated Gene 15 ISG15, a ubiquitin-like protein that covalently modifies protein substrates, a tightly regulated process in the context of innate immunity. In this study, using advanced mass spectrometry and chemical biology tools, we defined the USP18 Interactome and ISG15ylome in chronic myeloid leukemia (CML)-derived cells (HAP1) treated with Interferon alpha (IFNα). Novel ISG15ylation targets were characterized that reduce the sensing of innate ligands and secretion of cytokines. In addition, we show that USP18 deletion leads to enhanced ISG15ylation profiles. Furthermore, we demonstrate that CML USP18-/- cells are more antigenic, leading to increased activation of cytotoxic T lymphocytes (CTLs), and are more susceptible to irradiation. Our results reinforce the role of USP18 as a key “brake” for inflammatory signals in tumor cells. As USP18 expression is upregulated in lung, breast and colon cancers, USP18 pharmacological inhibition may reflect a target opportunity in cancer immunotherapy. Citation Format: Adan Pinto-Fernandez, Helene Greenwood, Mariolina Salio, Jianzhou Chen, Thomas Partridge, George Vere, Hannah C. Scott, Andreas Damianou, Persephone Borrow, Ruth Muschel, Vincenzo Cerundolo, Benedikt M. Kessler. USP18 modulates the ISGylome, immune signaling and sensitizes tumor cells to irradiation and CTL recognition [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-080.