Department of Medical Oncology, Inselspital, Bern University Hospital.
Department for BioMedical Research (DBMR).
JCI Insight. 2021 Dec 8;6(23):e151797. doi: 10.1172/jci.insight.151797.
Leukemia stem cells (LSCs) promote the disease and seem resistant to therapy and immune control. Why LSCs are selectively resistant against elimination by CD8+ cytotoxic T cells (CTLs) is still unknown. In this study, we demonstrate that LSCs in chronic myeloid leukemia (CML) can be recognized and killed by CD8+ CTLs in vitro. However, Tregs, which preferentially localized close to CD8+ CTLs in CML BM, protected LSCs from MHC class I-dependent CD8+ CTL-mediated elimination in vivo. BM Tregs in CML were characterized by the selective expression of tumor necrosis factor receptor 4 (Tnfrsf4). Stimulation of Tnfrsf4 signaling did not deplete Tregs but reduced the capacity of Tregs to protect LSCs from CD8+ CTL-mediated killing. In the BM of newly diagnosed CML patients, TNFRSF4 mRNA levels were significantly increased and correlated with the expression of the Treg-restricted transcription factor FOXP3. Overall, these results identify Tregs as key regulators of immune escape of LSCs and TNFRSF4 as a potential target to reduce the function of Tregs and boost antileukemic immunity in CML.
白血病干细胞（LSCs）促进疾病的发生，并且似乎对治疗和免疫控制具有抗性。为什么 LSCs 对 CD8+细胞毒性 T 细胞（CTLs）的消除具有选择性抗性仍然未知。在这项研究中，我们证明了慢性髓系白血病（CML）中的 LSCs 可以在体外被 CD8+CTL 识别和杀死。然而，Tregs 优先定位于 CML BM 中的 CD8+CTL 附近，在体内保护 LSCs 免受 MHC 类 I 依赖性 CD8+CTL 介导的消除。CML 中的 BM Tregs 表现出肿瘤坏死因子受体 4（Tnfrsf4）的选择性表达。刺激 Tnfrsf4 信号不会耗尽 Tregs，但会降低 Tregs 保护 LSCs 免受 CD8+CTL 介导杀伤的能力。在新诊断的 CML 患者的 BM 中，TNFRSF4 mRNA 水平显着增加，并与 Treg 限制性转录因子 FOXP3 的表达相关。总的来说，这些结果表明 Tregs 是 LSCs 免疫逃逸的关键调节剂，而 TNFRSF4 是减少 Tregs 功能并增强 CML 抗白血病免疫的潜在靶标。
