Chronic lymphocytic leukemia (CLL) is a B-cell neoplasia characterized by protumor immune dysregulation involving nonmalignant cells of the microenvironment, including T lymphocytes and tumor-associated myeloid cells. Although therapeutic agents have improved treatment options for CLL, many patients still fail to respond. Some patients also show immunosuppression. We have investigated trabectedin, a marine-derived compound with cytotoxic activity on macrophages in solid tumors. Here, we demonstrate that trabectedin induces apoptosis of human primary leukemic cells and also selected myeloid and lymphoid immunosuppressive cells, mainly through the TRAIL/TNF pathway. Trabectedin modulates transcription and translation of IL6, CCL2, and IFNα in myeloid cells and FOXP3 in regulatory T cells. Human memory CD8+ T cells downregulate PD-1 and, along with monocytes, exert in vivo antitumor function. In xenograft and immunocompetent CLL mouse models, trabectedin has antileukemic effects and antitumor impact on the myeloid and lymphoid cells compartment. It depletes myeloid-derived suppressor cells and tumor-associated macrophages and increases memory T cells. Trabectedin also blocks the PD-1/PD-L1 axis by targeting PD-L1+ CLL cells, PD-L1+ monocytes/macrophages, and PD-1+ T cells. Thus, trabectedin behaves as an immunomodulatory drug with potentially attractive therapeutic value in the subversion of the protumor microenvironment and in overcoming chemoimmune resistance.

中文翻译：

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Trabectedin揭示了慢性淋巴细胞白血病的免疫调节策略。

慢性淋巴细胞性白血病（CLL）是一种B细胞瘤样变，其特征是涉及微环境的非恶性细胞（包括T淋巴细胞和与肿瘤相关的髓样细胞）的肿瘤免疫异常。尽管治疗药物改善了CLL的治疗选择，但许多患者仍无反应。一些患者还表现出免疫抑制作用。我们研究了trabectedin，这是一种海洋来源的化合物，对实体瘤中的巨噬细胞具有细胞毒活性。在这里，我们证明trabectedin诱导人原发性白血病细胞凋亡，并且还主要通过TRAIL / TNF途径选择了髓样和淋巴样免疫抑制细胞。Trabectedin调节髓样细胞中IL6，CCL2和IFNα的转录和翻译，以及调节性T细胞中的FOXP3。人类记忆CD8 + T细胞下调PD-1，并且 与单核细胞一起，发挥体内抗肿瘤功能。在异种移植和具有免疫能力的CLL小鼠模型中，trabectedin对骨髓和淋巴样细胞区室具有抗白血病作用和抗肿瘤作用。它耗尽了髓样来源的抑制细胞和肿瘤相关的巨噬细胞，并增加了记忆T细胞。Trabectedin还通过靶向PD-L1 + CLL细胞，PD-L1 +单核细胞/巨噬细胞和PD-1 + T细胞来阻断PD-1 / PD-L1轴。因此，trabectedin表现为一种免疫调节药物，在颠覆肿瘤微环境和克服化学免疫耐药性方面具有潜在的诱人治疗价值。它耗尽了髓样来源的抑制细胞和肿瘤相关的巨噬细胞，并增加了记忆T细胞。Trabectedin还通过靶向PD-L1 + CLL细胞，PD-L1 +单核细胞/巨噬细胞和PD-1 + T细胞来阻断PD-1 / PD-L1轴。因此，trabectedin表现为一种免疫调节药物，在颠覆肿瘤微环境和克服化学免疫耐药性方面具有潜在的诱人治疗价值。它耗尽了髓样来源的抑制细胞和肿瘤相关的巨噬细胞，并增加了记忆T细胞。Trabectedin还通过靶向PD-L1 + CLL细胞，PD-L1 +单核细胞/巨噬细胞和PD-1 + T细胞来阻断PD-1 / PD-L1轴。因此，trabectedin表现为一种免疫调节药物，在颠覆肿瘤微环境和克服化学免疫耐药性方面具有潜在的诱人治疗价值。