Laboratorio de Inmunología Oncológica, Instituto de Medicina Experimental (IMEX), CONICET-Academia Nacional de Medicina (ANM), Pacheco de Melo 3081, 1425, Buenos Aires, Argentina.
Servicio de Hematología, Hospital General de Agudos Dr. Teodoro Álvarez, Buenos Aires, Argentina.
Cancer Immunol Immunother. 2020 May;69(5):813-824. doi: 10.1007/s00262-020-02513-y. Epub 2020 Feb 13.
Despite significant therapeutic improvements chronic lymphocytic leukemia (CLL) remains an incurable disease and there is a persistent pursuit of new treatment alternatives. Lurbinectedin, a selective inhibitor of active transcription of protein-coding genes, is currently in phase II/III clinical trials for solid tumors such as small-cell lung cancer (SCLC). In this study, we aimed to evaluate the activity of Lurbinectedin on circulating mononuclear cells from CLL patients and to determine whether Lurbinectedin could affect the cross-talk between B-CLL cells and the tumor microenvironment. We found that Lurbinectedin induced a dose- and time-dependent death in all cell types evaluated, with B cells, monocytes and monocytic myeloid derived suppressor cells (Mo-MDSC) being the most susceptible populations. At sub-apoptotic doses, Lurbinectedin decreased the expression of CCR7 in B-CLL cells and impaired their migration towards CCL19 and CCL21. Furthermore, low concentrations of Lurbinectedin stimulated the synthesis of pro-IL1β in monocytes and nurse-like cells, without inducing the inflammasome activation. Altogether, these results indicate that Lurbinectedin might have antitumor activity in CLL due to its direct action on leukemic cells in combination with its effects on the tumor microenvironment. Our findings encourage further investigation of Lurbinectedin as a potential therapy for CLL.
尽管慢性淋巴细胞白血病（CLL）的治疗有了显著的改善，但它仍然是一种无法治愈的疾病，因此人们一直在寻求新的治疗方法。Lurbinectedin 是一种蛋白编码基因活性转录的选择性抑制剂，目前正在进行用于小细胞肺癌（SCLC）等实体瘤的 II/III 期临床试验。在这项研究中，我们旨在评估 Lurbinectedin 对 CLL 患者循环单核细胞的活性，并确定 Lurbinectedin 是否能影响 B-CLL 细胞与肿瘤微环境之间的相互作用。我们发现，Lurbinectedin 在所有评估的细胞类型中均诱导剂量和时间依赖性的死亡，其中 B 细胞、单核细胞和单核细胞来源的髓系抑制细胞（Mo-MDSC）是最敏感的群体。在亚凋亡剂量下，Lurbinectedin 降低了 B-CLL 细胞中 CCR7 的表达，并损害了它们向 CCL19 和 CCL21 的迁移。此外，低浓度的 Lurbinectedin 刺激单核细胞和类滋养细胞中 pro-IL1β 的合成，而不会诱导炎症小体的激活。总的来说，这些结果表明，Lurbinectedin 可能因其对白血病细胞的直接作用以及对肿瘤微环境的影响而在 CLL 中具有抗肿瘤活性。我们的研究结果鼓励进一步研究 Lurbinectedin 作为 CLL 的潜在治疗方法。
