Trabectedin Reveals a Strategy of Immunomodulation in Chronic Lymphocytic Leukemia.

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 IFNα 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.

journal_name

Cancer Immunol Res

authors

Banerjee P,Zhang R,Ivan C,Galletti G,Clise-Dwyer K,Barbaglio F,Scarfò L,Aracil M,Klein C,Wierda W,Plunkett W,Caligaris-Cappio F,Gandhi V,Keating MJ,Bertilaccio MTS

doi

10.1158/2326-6066.CIR-19-0152

subject

Has Abstract

pub_date

2019-12-01 00:00:00

pages

2036-2051

issue

12

eissn

2326-6066

issn

2326-6074

pii

2326-6066.CIR-19-0152

journal_volume

7

pub_type

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