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.
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Chronic lymphocytic leukemia
Monocytic myeloid-derived suppressor cells
Phosphorylated extracellular signal-regulated kinase 1/2
Small-cell lung cancer
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The authors want to specially thank the patients and healthy donors who provided blood samples for this research. Also, we are indebted to Beatriz Loria, María Tejeda, Romina Pagano and Federico Fuentes for their technical assistance.
This work was supported by a Grant from FONCyT (PICT 212/2012), Ministry of Science, Technology and Innovation, Argentina.
Conflict of interest
The authors declare that they have no conflict of interest.
This research was conducted in accordance with the Helsinki Declaration. The study was approved on September 11th of 2012 and revalidated on April 11th of 2018 by the Institutional Review Board of the National Academy of Medicine, Buenos Aires, Argentina.
Peripheral blood samples were collected from CLL patients and healthy donors after written informed consent allowing the use of their specimens and data for research and for publication.
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Risnik, D., Colado, A., Podaza, E. et al. Immunoregulatory effects of Lurbinectedin in chronic lymphocytic leukemia. Cancer Immunol Immunother (2020). https://doi.org/10.1007/s00262-020-02513-y
- Chronic lymphocytic leukemia (CLL)
- Tumor microenvironment