Immunoregulatory effects of Lurbinectedin in chronic lymphocytic leukemia

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2020-05, Vol.69 (5), p.813-824
• Main Authors: Risnik, Denise, Colado, Ana, Podaza, Enrique, Almejún, María Belén, Elías, Esteban Enrique, Bezares, Raimundo Fernando, Fernández-Grecco, Horacio, Seija, Noé, Oppezzo, Pablo, Borge, Mercedes, Gamberale, Romina, Giordano, Mirta
• Format: Article
• Language: English
• Subjects: Antitumor activity; Apoptosis; Apoptosis - drug effects; Apoptosis - immunology; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Cancer Research; Carbolines - pharmacology; CCL19 protein; CCL21 protein; CCR7 protein; Cell death; Cell Survival - drug effects; Cell Survival - immunology; Chemokine CCL19 - immunology; Chemokine CCL19 - metabolism; Chemokine CCL21 - immunology; Chemokine CCL21 - metabolism; Chronic lymphocytic leukemia; Clinical trials; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - immunology; Heterocyclic Compounds, 4 or More Rings - pharmacology; Humans; Immunology; Immunoregulation; Inflammasomes; Interleukin 1; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - blood; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - immunology; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Leukocyte migration; Leukocytes (mononuclear); Lung cancer; Lymphatic leukemia; Lymphocytes B; Medicine; Medicine & Public Health; Monocytes; Monocytes - drug effects; Monocytes - immunology; Monocytes - metabolism; Myeloid-Derived Suppressor Cells - drug effects; Myeloid-Derived Suppressor Cells - immunology; Myeloid-Derived Suppressor Cells - metabolism; Oncology; Original; Original Article; Primary Cell Culture; Receptors, CCR7 - immunology; Receptors, CCR7 - metabolism; Small cell lung carcinoma; Solid tumors; Suppressor cells; Transcription; Tumor Cells, Cultured; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-020-02513-y

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.