Somatic USP8 alteration affects the immune landscape of corticotroph pituitary adenomas– a pilot study

Introduction: Somatic mutations in ubiquitin-specific protease-8 (USP8), encoding a deubiquinating protein, are found in approximately 30% of corticotroph-derived pituitary adenomas (CPAs). Stratifin, a protein encoded by SFN, inhibits USP8 catalytic activity. USP8 has immunomodulating properties that have been demonstrated in non-tumoral diseases. Methods: We assessed the influence of USP8 on the immune landscape of CPA and validated this effect and its dependency on stratifin in large cohorts of non-pituitary tumors. We analyzed data of CPA samples (n = 20) and additional non-pituitary tumors from the TCGA database, using transcriptome signature-recognition algorithms. Immune tumor microenvironment (iTME) was compared both by USP8 and SFN expression levels (n = 843) and by USP8 mutation status and SFN expression (n = 12,389). Results: CPA with activating USP8 mutations was associated with “cold” iTME compared with wild-type USP8 CPA, as reflected by lower fractions of immune cells, including 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 (3061 genes), included microglia pathogen phagocytosis and multiple toll-like receptor signaling pathways (p < 0.0001). In a validation analysis based on large cohorts of non-pituitary tumors, high expression of USP8 was associated with a suppressed iTME effect that was augmented by a low SFN expression. Conclusions: Our data demonstrate for the first time, to our knowledge, a distinct immune landscape of tumors based on USP8 status and expression and the dependency of this immunological effect on SFN expression.