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Immunoregulatory effects of Lurbinectedin in chronic lymphocytic leukemia

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Abstract

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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Abbreviations

CLL:

Chronic lymphocytic leukemia

HD:

Healthy donor

Mo-MDSC:

Monocytic myeloid-derived suppressor cells

NLC:

Nurse-like cells

P-Erk½:

Phosphorylated extracellular signal-regulated kinase 1/2

SCLC:

Small-cell lung cancer

TAM:

Tumor-associated macrophages

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Acknowledgements

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.

Funding

This work was supported by a Grant from FONCyT (PICT 212/2012), Ministry of Science, Technology and Innovation, Argentina.

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Authors and Affiliations

  1. Laboratorio de Inmunología Oncológica, Instituto de Medicina Experimental (IMEX), CONICET-Academia Nacional de Medicina (ANM), Pacheco de Melo 3081, 1425, Buenos Aires, Argentina

    Denise Risnik, Ana Colado, Enrique Podaza, María Belén Almejún, Esteban Enrique Elías, Mercedes Borge, Romina Gamberale & Mirta Giordano

  2. Servicio de Hematología, Hospital General de Agudos Dr. Teodoro Álvarez, Buenos Aires, Argentina

    Raimundo Fernando Bezares

  3. Servicio de Hematología, Sanatorio Julio Méndez, Buenos Aires, Argentina

    Horacio Fernández-Grecco

  4. Laboratorio de Leucemia Linfocítica Crónica, Institut Pasteur Montevideo, Montevideo, Uruguay

    Noé Seija & Pablo Oppezzo

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  1. Denise Risnik
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  2. Ana Colado
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Contributions

DR and MG designed the study. DR, AC, EP, MBA, NS and EEE performed the experiments. RFB and HF-G recruited patients and performed clinical analysis. DR, MB, PO, RG and MG analyzed the data. DR, AC and MG wrote the manuscript. All authors reviewed and approved the manuscript.

Corresponding author

Correspondence to Denise Risnik.

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The authors declare that they have no conflict of interest.

Ethical approval

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.

Informed consent

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 69, 813–824 (2020). https://doi.org/10.1007/s00262-020-02513-y

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