肿瘤细胞治疗研究
英文原题：CLL-Derived Extracellular Vesicles Impair T-Cell Activation and Foster T-Cell Exhaustion via Multiple Immunological Checkpoints.
背景：慢性淋巴细胞白血病（CLL）以恶性B细胞克隆扩增和多种免疫缺陷为特征。
背景：慢性淋巴细胞白血病（CLL）以恶性B细胞克隆扩增和多种免疫缺陷为特征。这尤其导致严重的感染性并发症和免疫监视效率低下。CLL中的T细胞缺陷包括免疫（代谢）耗竭增强、活化和细胞因子产生受损以及免疫突触畸形。与此同时，多项研究已报道CLL细胞与T细胞之间的相互作用最终导致T细胞功能障碍。然而，其相互作用的复杂全貌尚未被完全理解。在此，我们聚焦于CLL细胞来源的囊泡（EVs），已知其具有免疫调节作用，对T细胞功能的影响。方法：我们对CLL细胞分泌的EVs进行了表征，并确定了它们在存活、活化、（代谢）适应性和功能方面对T细胞的影响。结果：我们发现CLL-EVs损害T细胞活力、增殖、活化和代谢，同时促进其耗竭和调节性T细胞亚群的形成。对CLL-EV货物的详细分析揭示了大量免疫检查点（ICs），这可以解释所检测到的T细胞失调。结论：鉴定出CLL-EVs上负载的多种ICs可能解释CLL患者中的T细胞缺陷，并可能代表IC阻断或过继性T细胞转移等免疫疗法的障碍。我们的发现可能为通过同时靶向EV形成或多种ICs来改善抗肿瘤免疫铺平道路。
Background: Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of malignant B-cells and multiple immune defects. This leads, among others, to severe infectious complications and inefficient immune surveillance. T-cell deficiencies in CLL include enhanced immune(-metabolic) exhaustion, impaired activation and cytokine production, and immunological synapse malformation. Several studies have meanwhile reported CLL-cell-T-cell interactions that culminate in T-cell dysfunction. However, the complex entirety of their interplay is incompletely understood. Here, we focused on the impact of CLL cell-derived vesicles (EVs), which are known to exert immunoregulatory effects, on T-cell function. Methods: We characterized EVs secreted by CLL-cells and determined their influence on T-cells in terms of survival, activation, (metabolic) fitness, and function. Results: We found that CLL-EVs hamper T-cell viability, proliferation, activation, and metabolism while fostering their exhaustion and formation of regulatory T-cell subsets. A detailed analysis of the CLL-EV cargo revealed an abundance of immunological checkpoints (ICs) that could explain the detected T-cell dysregulations. Conclusions: The identification of a variety of ICs loaded on CLL-EVs may account for T-cell defects in CLL patients and could represent a barrier for immunotherapies such as IC blockade or adoptive T-cell transfer. Our findings could pave way for improving antitumor immunity by simultaneously targeting EV formation or multiple ICs.
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