Pan-cancer analysis reveals context-dependent roles of LINE-1 ORF1p in immune regulation and copy number alterations

L1 comprises 17% of the human genome, with 50-150 full-length sequences capable of retrotransposition. Although largely inactive in normal somatic tissues, tumorigenesis leads to L1 derepression and overexpression of its RNA binding chaperone protein, ORF1p. A potential cancer biomarker, ORF1p expression is a hallmark of multiple cancers and an early event in precursor lesions. Our study provides a comprehensive pan-cancer analysis of ORF1p using CPTAC proteogenomic data, revealing a dichotomous role in modulating immune responses. Integrated analyses and supervised learning models divide ORF1p-high tumors into two groups: (1) high ORF1p associates with immunosuppression, reduced interferon signaling and diminished immune cell infiltration (HNSCC and LSCC), and (2) ORF1p-high tumors associate with immune activation (UCEC). Linear regression models reveal that cancer-specific aneuploidies may underlie this immune dichotomy, highlighting the prognostic significance of ORF1p and informing new strategies to leverage detection of plasma-circulating ORF1p to enhance immunotherapeutic efficacy in different tumor contexts.