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Somatic USP8 alteration affects the immune landscape of corticotroph pituitary adenomas- a pilot study
Dahlia Greidinger1,2, Reut Halperin1,3, Roni Zemet1,4
1Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel.
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.
Insights
Somatic mutations in ubiquitin-specific protease-8 (USP8) influence the tumor immune microenvironment (iTME) in pituitary adenomas, creating a "cold" iTME. This effect is dependent on stratifin (SFN) expression, particularly in non-pituitary tumors.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Somatic mutations in ubiquitin-specific protease-8 (USP8) are prevalent in corticotroph-derived pituitary adenomas (CPAs).
- Stratifin (SFN) is known to inhibit USP8 activity.
- USP8 possesses immunomodulating properties relevant to non-tumoral conditions.
Purpose of the Study:
- To investigate the impact of USP8 on the immune landscape of CPA.
- To validate the influence of USP8 on the immune microenvironment and its dependence on SFN in broader tumor cohorts.
Main Methods:
- Analysis of CPA samples (n=20) and large non-pituitary tumor cohorts (n=843 and n=12,389) from TCGA.
- Utilized transcriptome signature-recognition algorithms to assess the immune tumor microenvironment (iTME).
- Compared iTME based on USP8 and SFN expression levels and USP8 mutation status.
Main Results:
- CPA with activating USP8 mutations exhibited a "cold" iTME, characterized by reduced immune cell infiltration compared to wild-type CPA.
- USP8 mutations altered pathways including microglia pathogen phagocytosis and toll-like receptor signaling.
- High USP8 expression correlated with suppressed iTME in non-pituitary tumors, an effect amplified by low SFN expression.
Conclusions:
- This study reveals a distinct tumor immune landscape associated with USP8 status and expression.
- The immunomodulatory effect of USP8 is significantly dependent on SFN expression.
- Findings provide novel insights into the interplay between USP8, SFN, and the tumor immune microenvironment across various cancer types.
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