BCL-2 表达通过增强调节性 T 细胞分化和细胞毒性 T 细胞耗竭促进慢性淋巴细胞白血病中的免疫抑制。
BCL-2 expression promotes immunosuppression in chronic lymphocytic leukemia by enhancing regulatory T cell differentiation and cytotoxic T cell exhaustion.
机构信息
Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China.
Key Laboratory of Hematology of Nanjing Medical University, Nanjing, 210029, China.
出版信息
Mol Cancer. 2022 Feb 22;21(1):59. doi: 10.1186/s12943-022-01516-w.
BACKGROUND
Chronic lymphocytic leukemia (CLL) results in increased susceptibility to infections. T cell dysfunction is not associated with CLL in all patients; therefore, it is important to identify CLL patients with T cell defects. The role of B-cell lymphoma-2 (BCL-2) in CLL has been explored; however, few studies have examined its role in T cells in CLL patients. Herein, we have investigated the regulatory role of BCL-2 in T cells in the CLL tumor microenvironment.
METHODS
The expression of BCL-2 in T cells was evaluated using flow cytometry. The regulatory roles of BCL-2 were investigated using single-cell RNA sequencing (scRNA-seq) and verified using multi-parameter flow cytometry on CD4 and CD8 T cells. The clinical features of BCL-2 expression in T cells in CLL were also explored.
RESULTS
We found a significant increase in BCL-2 expression in the T cells of CLL patients (n = 266). Single cell RNA sequencing (scRNA-seq) indicated that BCL-2CD4 T cells had the gene signature of increased regulatory T cells (Treg); BCL-2CD8 T cells showed the gene signature of exhausted cytotoxic T lymphocytes (CTL); and increased expression of BCL-2 was associated with T cell activation and cellular adhesion. The results from scRNA-seq were verified in peripheral T cells from 70 patients with CLL, wherein BCL-2CD4 T cells were enriched with Tregs and had higher expression of interleukin-10 and transforming growth factor-β than BCL-2CD4 T cells. BCL-2 expression in CD8T cells was associated with exhausted cells (PD-1Tim-3) and weak expression of granzyme B and perforin. T cell-associated cytokine profiling revealed a negative association between BCL-2 T cells and T cell activation. Decreased frequencies and recovery functions of BCL-2T cells were observed in CLL patients in complete remission after treatment with venetoclax.
CONCLUSION
BCL-2 expression in the T cells of CLL patients is associated with immunosuppression via promotion of Treg abundance and CTL exhaustion.
背景
慢性淋巴细胞白血病（CLL）会导致患者更容易感染。并非所有 CLL 患者都存在 T 细胞功能障碍；因此，识别 CLL 患者的 T 细胞缺陷非常重要。B 细胞淋巴瘤-2（BCL-2）在 CLL 中的作用已被探索；然而，很少有研究检查其在 CLL 患者 T 细胞中的作用。在此，我们研究了 BCL-2 在 CLL 肿瘤微环境中对 T 细胞的调节作用。
方法
使用流式细胞术评估 T 细胞中 BCL-2 的表达。通过单细胞 RNA 测序（scRNA-seq）研究 BCL-2 的调节作用，并使用多参数流式细胞术在 CD4 和 CD8 T 细胞上验证。还探讨了 CLL 患者 T 细胞中 BCL-2 表达的临床特征。
结果
我们发现 CLL 患者（n=266）T 细胞中 BCL-2 的表达显著增加。单细胞 RNA 测序（scRNA-seq）表明 BCL-2CD4 T 细胞具有调节性 T 细胞（Treg）增加的基因特征；BCL-2CD8 T 细胞显示耗竭细胞毒性 T 淋巴细胞（CTL）的基因特征；BCL-2 的高表达与 T 细胞激活和细胞黏附有关。来自 70 名 CLL 患者外周 T 细胞的 scRNA-seq 结果得到了验证，其中 BCL-2CD4 T 细胞富含 Treg，且表达的白细胞介素-10 和转化生长因子-β高于 BCL-2CD4 T 细胞。CD8T 细胞中 BCL-2 的表达与耗竭细胞（PD-1Tim-3）和颗粒酶 B 和穿孔素的弱表达有关。T 细胞相关细胞因子谱分析显示 BCL-2 T 细胞与 T 细胞激活呈负相关。在接受 venetoclax 治疗后完全缓解的 CLL 患者中，BCL-2T 细胞的频率和恢复功能降低。
结论
CLL 患者 T 细胞中 BCL-2 的表达通过促进 Treg 丰度和 CTL 耗竭与免疫抑制有关。
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