TY - JOUR
T1 - Trabectedin reveals a strategy of immunomodulation in chronic lymphocytic leukemia
AU - Banerjee, Priyanka
AU - Zhang, Ronghua
AU - Ivan, Cristina
AU - Galletti, Giovanni
AU - Clise-Dwyer, Karen
AU - Barbaglio, Federica
AU - Scarfó, Lydia
AU - Aracil, Miguel
AU - Klein, Christian
AU - Wierda, William
AU - Plunkett, William
AU - Caligaris-Cappio, Federico
AU - Gandhi, Varsha
AU - Keating, Michael J.
AU - Bertilaccio, Maria Teresa S.
N1 - Funding Information:
This study was supported by the CLL Global Research Foundation (to M.T.S. Bertilaccio and V. Gandhi), The University of Texas MD Anderson Cancer Center Moon Shots Program (to M.T.S. Bertilaccio, V. Gandhi, and M.J. Keating), Roche (to M.T.S. Bertilaccio), NCI P30CA016672 (to the South Campus Flow Cytometry and Cell Sorting Core MD Anderson Cancer Center), and Program Molecular Clinical Oncology-5 per mille number 9965 (to F. Caligaris-Cappio), Associazione Italiana per la Ricerca sul Cancro (AIRC, Italy). Em-TCL1 transgenic micewerefromJ.ByrdandC.M.Croce(Columbus,OH).Rag2−/−gc−/−miceon BALB/c background were provided by CIEA (Kawasaki, Japan) and Taconic. The authors thank PharmaMar, S.A., for providing trabectedin, and the Department of Scientific Publications, MD Anderson Cancer Center, for reviewing the manuscript and providing constructive comments. Figures were produced using Servier Medical Art: www.servier.com.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
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U2 - 10.1158/2326-6066.CIR-19-0152
DO - 10.1158/2326-6066.CIR-19-0152
M3 - Article
C2 - 31530560
AN - SCOPUS:85076063383
SN - 2326-6066
VL - 7
SP - 2036
EP - 2051
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 12
ER -