Immunoregulatory effects of Lurbinectedin in chronic lymphocytic leukemia

• DOI: 10.1007/s00262-020-02513-y
• Publication Date: 2020-02-13T11:02:52Z
• Authors: Denise Risnik; Ana Colado; Enrique Podaza; María Belén Almejún; Esteban Enrique E...; Raimundo Fernando...; Horacio Fernández...; Noé Seija; Pablo Oppezzo; Mercedes Borge; Romina Gamberale; Mirta Giordano
• Keywords: Lurbinectedin; 0301 basic medicine; Receptors, CCR7; Cell Survival; Primary Cell Culture; Apoptosis; Heterocyclic Compounds, 4 or More Rings; Monocytes; 03 medical and health sciences; https://purl.org/becyt/ford/3.1; Tumor Cells, Cultured; Tumor Microenvironment; Humans; https://purl.org/becyt/ford/3; B-Lymphocytes; Chemokine CCL21; Myeloid-Derived Suppressor Cells; Leukemia, Lymphocytic, Chronic, B-Cell; Chronic lymphocytic leukemia (CLL); 3. Good health; Gene Expression Regulation, Neoplastic; Tumor microenvironment; Chemokine CCL19; IL1β; Drug Screening Assays, Antitumor; CCR7; Carbolines

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.