Characterizing the tumor immune environment in thymic epithelial tumors using T-cell receptor repertoire analysis and gene expression profiling

Abstract

Objectives

A thymoma is a functional thymic epithelial tumor wherein tumorigenic thymic epithelial cells possess T-cell differentiation and maturation potential. The tumor immune environment exhibits heterogeneous tumor immunity. The tumor immune environment of thymoma is characterized by its distinctive and complex immunological functions, requiring an analysis of the various factors involved. We aimed to evaluate the thymoma tumor immune environment and conduct a comprehensive immunogenomic profiling.

Methods

Ninety-seven patients undergoing surgery for primary thymoma were enrolled in the study. RNA was extracted from frozen tissue specimens, followed by analysis of T-cell receptor repertoire and RNA-seq. A clonality assessment of the T-cell receptor repertoire and shared clonotypes was also conducted. Gene expression profiling using digital cytometry (CIBERSORTx), T-cell inflammation signature, and Immunogram methodologies was performed.

Results

The analysis of T-cell receptor repertoire results indicated a higher level of clonality in B3 thymomas than in other histological types. The high-clonality group exhibited a worse prognosis than the low-clonality group. The results of digital cytometry revealed that type B3 thymomas were clustered and distinguished by a higher abundance of activated natural killer cells, macrophages, and resting mast cells than in other histological types. Additionally, the Immunogram gene signatures showed no correlation with the clonality of the T-cell receptor repertoire.

Conclusions

Multiple immunological approaches to evaluate the tumor immune environment and immunogenomic profile of thymoma reveal a diverse and complex immune environment. B3 thymomas, despite being T-cell depleted, exhibit increased T-cell receptor clonality and expanded T-cell clones. Given the poor prognosis and the elevated expression of T-cell inhibitory markers, particularly CTLA4, this subset of patients may represent a critical target population for future clinical trials investigating T-cell checkpoint inhibitors.