Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China.
Front Immunol. 2022 Sep 23;13:985280. doi: 10.3389/fimmu.2022.985280. eCollection 2022.
T cell immune dysfunction is a prominent characteristic of chronic lymphocytic leukemia (CLL) and the main cause of failure for immunotherapy and multi-drug resistance. There remains a lack of specific biomarkers for evaluating T cell immune status with outcome for CLL patients. T cell factor 1 (TCF1, encoded by the gene) can be used as a critical determinant of successful anti-tumor immunotherapy and a prognostic indicator in some solid tumors; however, the effects of TCF1 in CLL remain unclear. Here, we first analyzed the biological processes and functions of TCF1 and co-expressing genes using the GEO and STRING databases with the online tools Venny, Circos, and Database for Annotation, Visualization, and Integrated Discovery (DAVID). Then the expression and prognostic values of TCF1 and its partner gene B cell leukemia/lymphoma 11B (BCL11B) were explored for 505 CLL patients from 6 datasets and validated with 50 CLL patients from Henan cancer hospital (HNCH). TCF1 was downregulated in CLL patients, particularly in CD8+ T cells, which was significantly correlated with poor time-to-first treatment (TTFT) and overall survival (OS) as well as short restricted mean survival time (RMST). Function and pathway enrichment analysis revealed that TCF1 was positively correlated with BCL11B, which is involved in regulating the activation and differentiation of T cells in CLL patients. Intriguingly, BCL11B was highly consistent with TCF1 in its decreased expression and prediction of poor prognosis. More importantly, the combination of TCF1 and BCL11B could more accurately assess prognosis than either alone. Additionally, decreased TCF1 and BCL11B expression serves as an independent risk factor for rapid disease progression, coinciding with high-risk indicators, including unmutated IGHV, TP53 alteration, and advanced disease. Altogether, this study demonstrates that decreased TCF1 and BCL11B expression is significantly correlated with poor prognosis, which may be due to decreased TCF1+CD8+ T cells, impairing the effector CD8+ T cell differentiation regulated by TCF1/BCL11B.
T 细胞免疫功能障碍是慢性淋巴细胞白血病（CLL）的一个突出特征，也是免疫治疗和多药耐药失败的主要原因。目前仍然缺乏用于评估 CLL 患者 T 细胞免疫状态和预后的特异性生物标志物。T 细胞因子 1（TCF1，由 基因编码）可用作抗肿瘤免疫治疗成功的关键决定因素和某些实体瘤的预后指标；然而，TCF1 在 CLL 中的作用尚不清楚。在这里，我们首先使用 GEO 和 STRING 数据库以及在线工具 Venny、Circos 和数据库注释、可视化和综合发现（DAVID）分析了 TCF1 和共表达基因的生物学过程和功能。然后，我们探索了 505 例来自 6 个数据集的 CLL 患者中 TCF1 和其伙伴基因 B 细胞白血病/淋巴瘤 11B（BCL11B）的表达和预后价值，并在 50 例来自河南肿瘤医院（HNCH）的 CLL 患者中进行了验证。TCF1 在 CLL 患者中下调，特别是在 CD8+T 细胞中，与不良首次治疗时间（TTFT）和总生存期（OS）以及较短的限制性平均生存时间（RMST）显著相关。功能和途径富集分析表明，TCF1 与 BCL11B 呈正相关，BCL11B 参与调节 CLL 患者 T 细胞的激活和分化。有趣的是，BCL11B 与 TCF1 的表达下调和预后不良高度一致。更重要的是，TCF1 和 BCL11B 的组合比单独使用更能准确评估预后。此外，TCF1 和 BCL11B 表达的降低是疾病快速进展的独立危险因素，与高危指标一致，包括未突变的 IGHV、TP53 改变和晚期疾病。总的来说，这项研究表明，TCF1 和 BCL11B 表达的降低与预后不良显著相关，这可能是由于 TCF1+CD8+T 细胞减少，破坏了 TCF1/BCL11B 调节的效应 CD8+T 细胞分化。
