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

Hiroto Ishida MD , So Takata MD, PhD , Koichiro Aya PhD , Yoichiro Nakatani PhD , Masafumi Horie MD, PhD , Daichi Maeda MD, PhD , Soichiro Funaki MD, PhD , Yasushi Shintani MD, PhD , Shinichi Yachida MD, PhD
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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.
利用t细胞受体库分析和基因表达谱表征胸腺上皮肿瘤的肿瘤免疫环境
目的胸腺瘤是一种功能性胸腺上皮性肿瘤,其致瘤性胸腺上皮细胞具有t细胞分化和成熟潜能。肿瘤免疫环境表现为异质性肿瘤免疫。胸腺瘤的肿瘤免疫环境以其独特而复杂的免疫功能为特点,需要对涉及的各种因素进行分析。我们的目的是评估胸腺瘤肿瘤的免疫环境,并进行全面的免疫基因组分析。方法对97例原发性胸腺瘤手术患者进行研究。从冷冻组织标本中提取RNA,然后分析t细胞受体库和RNA-seq。还进行了t细胞受体库和共享克隆型的克隆性评估。使用数字细胞术(CIBERSORTx)、t细胞炎症特征和免疫图方法进行基因表达谱分析。结果t细胞受体库分析结果表明,B3型胸腺瘤的克隆水平高于其他组织学类型。高克隆组预后较低克隆组差。数字细胞术的结果显示,B3型胸腺瘤聚集并以激活的自然杀伤细胞、巨噬细胞和静止肥大细胞的丰度高于其他组织学类型来区分。此外,免疫图基因标记显示与t细胞受体库的克隆性无关。结论多种免疫学方法评价胸腺瘤的肿瘤免疫环境和免疫基因组谱,揭示了胸腺瘤的免疫环境的多样性和复杂性。B3胸腺瘤,尽管t细胞减少,但表现出增加的t细胞受体克隆性和扩增的t细胞克隆。鉴于预后不良和t细胞抑制标志物(特别是CTLA4)的表达升高,这部分患者可能是未来研究t细胞检查点抑制剂的临床试验的关键目标人群。
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CiteScore
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