LINE-1 ORF1p Mimics Viral Innate Immune Evasion Mechanisms in Pancreatic Ductal Adenocarcinoma

作者：Eunae You, Bidish K. Patel, Alexandra S. Rojas, Siyu Sun, Patrick Danaher, Natalie I. Ho, Ildiko E. Phillips, Michael J. Raabe, Yuhui Song, Katherine H. Xu, Joshua R. Kocher, Peter Richieri, Phoebe Shin, Martin S. Taylor, Linda T. Nieman, Benjamin D. Greenbaum, David T. Ting · 发表于：Cancer Discovery · 年份：2025 · DOI：10.1158/2159-8290.cd-24-1317 · 被引用次数：18 · 研究领域：interferon and immune responses、Animal Virus Infections Studies、Immunotherapy and Immune Responses

Abstract Repeat element viral mimicry is a common feature in pancreatic ductal adenocarcinoma (PDAC) that requires mechanisms to manage this repeat “viral” load and attenuate innate immune responses. In this study, we show that the long interspersed nuclear element 1 (LINE-1) open reading frame 1 protein (ORF1p) in PDAC cells plays a role in shielding repeat RNAs from activating a pathogen recognition receptor–mediated antiviral response that is independent of retrotransposition. Suppression of ORF1p using short hairpin RNA induces innate immune responses through the double-stranded RNA (dsRNA) sensors RIG-I and MAVS. Low ORF1p PDAC cell lines have suppressed expression of pathogen recognition receptors demonstrating convergent mechanisms to suppress innate immune signaling. Localization of ORF1p in processing bodies with the dsRNA helicase MOV10 was found to be important for these antiviral responses. Loss of ORF1p resulted in significant growth reduction in tumorspheres and mouse xenografts with an enriched epithelial cell state, and high ORF1p expression was associated with worsened survival in a cohort of human patients with PDAC. Significance: This study uncovers PDAC-specific mechanisms that dampen immune responses to viral-repeat RNA via long interspersed nuclear element 1 ORF1p. Suppression of ORF1p activates antiviral responses, reducing tumor growth and epithelial–mesenchymal transition. High ORF1p expression correlates with poor prognosis, highlighting its potentia...