Department of Internal Medicine 5 for Hematology and Oncology, Universitätsklinikum Erlangen, Erlangen, Bayern, Germany
Department of Internal Medicine 5 for Hematology and Oncology, Universitätsklinikum Erlangen, Erlangen, Bayern, Germany.
J Immunother Cancer. 2021 Apr;9(4). doi: 10.1136/jitc-2020-001889.
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Emerging data suggest that CLL-cells efficiently evade immunosurveillance. T-cell deficiencies in CLL include immuno(metabolic) exhaustion that is achieved by inhibitory molecules, with programmed cell death 1/programmed cell death ligand 1 (PD-L1) signaling emerging as a major underlying mechanism. Moreover, CLL-cells are characterized by a close and recurrent interaction with their stromal niches in the bone marrow and lymph nodes. Here, they receive nurturing signals within a well-protected environment. We could previously show that the interaction of CLL-cells with stroma leads to c-Myc activation that is followed by metabolic adaptations. Recent data indicate that c-Myc also controls expression of the immune checkpoint molecule PD-L1. Therefore, we sought out to determine the role of stromal contact for the CLL-cells' PD-L1 expression and thus their immuno-evasive phenotype.To do so, we analyzed PD-L1 expression on CLL cell (subsets) in untreated patients and on healthy donor-derived B-cells. Impact of stromal contact on PD-L1 expression on CLL-cells and the underlying signaling pathways were assessed in well-established in vitro niche models. Ex vivo and in vitro findings were validated in the Eµ-TCL1 transgenic CLL mouse model.We found increased PD-L1 expression on CLL-cells as compared with B-cells that was further enhanced in a cell-to-cell contact-dependent manner by stromal cells. In fact, circulating recent stromal-niche emigrants displayed higher PD-L1 levels than long-time circulating CLL-cells. Using our in vitro niche model, we show that a novel Notch-c-Myc-enhancer of zeste homolog 2 (EZH2) signaling axis controls PD-L1 upregulation. Ultimately, elevated PD-L1 levels conferred increased resistance towards activated autologous T-cells.In summary, our findings support the notion that the CLL microenvironment contributes to immune escape variants. In addition, several targetable molecules (eg, Notch or EZH2) could be exploited in view of improving immune responses in patients with CLL, which warrants further in-depth investigation.
慢性淋巴细胞白血病（CLL）是成人中最常见的白血病。新出现的数据表明，CLL 细胞能够有效地逃避免疫监视。CLL 中的 T 细胞缺陷包括免疫（代谢）衰竭，这是通过抑制分子实现的，程序性细胞死亡 1/程序性细胞死亡配体 1（PD-L1）信号转导成为主要的潜在机制。此外，CLL 细胞的特征是与骨髓和淋巴结中的基质龛密切且反复相互作用。在那里，它们在受到良好保护的环境中接收滋养信号。我们之前已经表明，CLL 细胞与基质的相互作用导致 c-Myc 激活，随后发生代谢适应。最近的数据表明，c-Myc 还控制免疫检查点分子 PD-L1 的表达。因此，我们试图确定基质接触对 CLL 细胞 PD-L1 表达及其免疫逃避表型的作用。为此，我们分析了未经治疗的患者中 CLL 细胞（亚群）和健康供体衍生 B 细胞上的 PD-L1 表达。在成熟的体外龛模型中评估了基质接触对 CLL 细胞 PD-L1 表达和潜在信号通路的影响。在 Eµ-TCL1 转基因 CLL 小鼠模型中验证了体外和体外的发现。我们发现与 B 细胞相比，CLL 细胞上的 PD-L1 表达增加，并且通过基质细胞以细胞间接触依赖的方式进一步增强。实际上，循环的最近基质龛移民显示出比长时间循环的 CLL 细胞更高的 PD-L1 水平。使用我们的体外龛模型，我们表明一种新型的 Notch-c-Myc-增强子 of zeste 同源物 2（EZH2）信号轴控制 PD-L1 的上调。最终，升高的 PD-L1 水平赋予对激活的自体 T 细胞更高的抵抗力。总之，我们的发现支持这样一种观点，即 CLL 微环境有助于免疫逃避变体。此外，一些可靶向的分子（例如 Notch 或 EZH2）可用于提高 CLL 患者的免疫反应，这需要进一步深入研究。
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