USP8 Status Affects the Immune Landscape of Corticotroph Pituitary Adenomas

Abstract Purpose Activating somatic mutations in ubiquitin-specific protease-8 (USP8), encoding a deubiquitinating protein, are found in approximately 30% of corticotroph-derived pituitary adenomas (CPA). USP8 has immunomodulating properties that were demonstrated in non-tumoral diseases. Our study aims to assess the influence of USP8 mutation status on the immune tumor microenvironment (iTME) of CPAs. Methods We analyzed 20 PCAs by RNA sequencing. In six of them, USP8 mutations were detected. We assessed the immune landscape of tumors by quantifying 22 immune cell types based on the CIBERSORT transcriptome signature-recognition algorithms. Also, we performed a pathway analysis for genes that were differentially expressed between groups using the Wikipathways 2019 and Reactome 2016 databases and using the EnrichR platform results. Results CPA with activating USP8 mutations were associated with "cold" iTME compared with wild type USP8 CPA. This "cold" iTME was reflected by lower fractions of B cells, CD4, regulatory and gamma/delta T cells, natural killer cells, M0 and M1 macrophages, dendritic cells and eosinophils (p < 0.05 for all comparisons). Pathways altered by the presence of USP8 mutation, based on the most differentially expressed genes (3,061 genes) included Microglia Pathogen Phagocytosis and multiple toll-like receptor signaling pathways (p < 0.0001). Conclusion USP8 status affects the immune landscape of corticotroph pituitary adenomas, with USP8 mutation associated with "cold" iTME.