Trabectedin reveals a strategy of immunomodulation in chronic lymphocytic leukemia

Priyanka Banerjee, Ronghua Zhang, Cristina Ivan, Giovanni Galletti, Karen Clise-Dwyer, Federica Barbaglio, Lydia Scarfó, Miguel Aracil, Christian Klein, William Wierda, William Plunkett, Federico Caligaris-Cappio, Varsha Gandhi, Michael J. Keating, Maria Teresa S. Bertilaccio

Research output: Contribution to journalArticle

Abstract

Chronic lymphocytic leukemia (CLL) is a B-cell neoplasia characterized by protumor immune dysregulation involving nonmalignant cells of the microenvironment, including T lymphocytes and tumor-associated myeloid cells. Although therapeutic agents have improved treatment options for CLL, many patients still fail to respond. Some patients also show immunosuppression. We have investigated trabectedin, a marine-derived compound with cytotoxic activity on macrophages in solid tumors. Here, we demonstrate that trabectedin induces apoptosis of human primary leukemic cells and also selected myeloid and lymphoid immunosuppressive cells, mainly through the TRAIL/TNF pathway. Trabectedin modulates transcription and translation of IL6, CCL2, and IFNa in myeloid cells and FOXP3 in regulatory T cells. Human memory CD8+ T cells downregulate PD-1 and, along with monocytes, exert in vivo antitumor function. In xenograft and immunocompetent CLL mouse models, trabectedin has antileukemic effects and antitumor impact on the myeloid and lymphoid cells compartment. It depletes myeloid-derived suppressor cells and tumor-associated macrophages and increases memory T cells. Trabectedin also blocks the PD-1/ PD-L1 axis by targeting PD-L1+ CLL cells, PD-L1+ monocytes/ macrophages, and PD-1+ T cells. Thus, trabectedin behaves as an immunomodulatory drug with potentially attractive therapeutic value in the subversion of the protumor microenvironment and in overcoming chemoimmune resistance.

Original languageEnglish
Pages (from-to)2036-2051
Number of pages16
JournalCancer immunology research
Volume7
Issue number12
DOIs
Publication statusPublished - Jan 1 2019

    Fingerprint

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

Banerjee, P., Zhang, R., Ivan, C., Galletti, G., Clise-Dwyer, K., Barbaglio, F., Scarfó, L., Aracil, M., Klein, C., Wierda, W., Plunkett, W., Caligaris-Cappio, F., Gandhi, V., Keating, M. J., & Bertilaccio, M. T. S. (2019). Trabectedin reveals a strategy of immunomodulation in chronic lymphocytic leukemia. Cancer immunology research, 7(12), 2036-2051. https://doi.org/10.1158/2326-6066.CIR-19-0152