TY - JOUR
T1 - Trabectedin overcomes doxorubicin-resistance, counteracts tumor-immunosuppressive reprogramming of monocytes and decreases xenograft growth in Hodgkin lymphoma
AU - Casagrande, Naike
AU - Borghese, Cinzia
AU - Favero, Andrea
AU - Vicenzetto, Cristina
AU - Aldinucci, Donatella
N1 - Funding Information:
This work was supported in part by grant IG 15844 from the Italian Association for Cancer Research (D.A.) and by Italian Ministry of Health (Ricerca Corrente) [no grant number provided]. The authors thank Dr. Barbara Belletti for her support for in vivo mice experiments, Valerie Matarese who provided scientific editing and Alfonso Colombatti for its help to review the manuscript.
Publisher Copyright:
© 2020 Elsevier B.V.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2021/3/1
Y1 - 2021/3/1
N2 - Classical Hodgkin lymphoma (cHL) tumor cells are surrounded by a protective tumor microenvironment (TME). Trabectedin, an anticancer drug targeting both tumor cells and TME, demonstrated a potent antitumor activity against Hodgkin Reed Sternberg (HRS) cells. It was cytotoxic against cHL cell lines, including the doxorubicin-resistant clones, with subnanomolar IC50 values, and inhibited clonogenic growth and heterospheroid cell viability. It induced necroptosis, caused DNA damage, G2/M cell cycle arrest, and increased reactive oxygen species production. It reduced HRS cell secretion of CCL5, M-CSF, IL-6, IL-13 and TARC, and inhibited migration. Conditioned medium from trabectedin-treated HRS cells was less chemoattractive toward monocytes, mesenchymal stromal cells and lymphocytes, and less effective in educating monocytes to become immunosuppressive macrophages. These monocytes expressed lower levels of indoleamine 2,3-dioxygenase-1, CD206 and PD-L1, secreted lower amounts of IL-10, TARC, and TGF-β, and were less able to inhibit the growth of activated lymphocytes. In vivo, trabectedin inhibited by >75% the growth of cHL murine xenografts with minimal weight loss; tumors of trabectedin-treated mice had fewer TAMs and less angiogenesis. Altogether, this study offers a preclinical rationale for trabectedin use as a new drug candidate in relapsed/refractory cHL patients.
AB - Classical Hodgkin lymphoma (cHL) tumor cells are surrounded by a protective tumor microenvironment (TME). Trabectedin, an anticancer drug targeting both tumor cells and TME, demonstrated a potent antitumor activity against Hodgkin Reed Sternberg (HRS) cells. It was cytotoxic against cHL cell lines, including the doxorubicin-resistant clones, with subnanomolar IC50 values, and inhibited clonogenic growth and heterospheroid cell viability. It induced necroptosis, caused DNA damage, G2/M cell cycle arrest, and increased reactive oxygen species production. It reduced HRS cell secretion of CCL5, M-CSF, IL-6, IL-13 and TARC, and inhibited migration. Conditioned medium from trabectedin-treated HRS cells was less chemoattractive toward monocytes, mesenchymal stromal cells and lymphocytes, and less effective in educating monocytes to become immunosuppressive macrophages. These monocytes expressed lower levels of indoleamine 2,3-dioxygenase-1, CD206 and PD-L1, secreted lower amounts of IL-10, TARC, and TGF-β, and were less able to inhibit the growth of activated lymphocytes. In vivo, trabectedin inhibited by >75% the growth of cHL murine xenografts with minimal weight loss; tumors of trabectedin-treated mice had fewer TAMs and less angiogenesis. Altogether, this study offers a preclinical rationale for trabectedin use as a new drug candidate in relapsed/refractory cHL patients.
KW - Doxorubicin
KW - Hodgkin lymphoma
KW - Trabectedin
KW - Tumor associated macrophages
KW - Tumor microenvironment
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U2 - 10.1016/j.canlet.2020.12.015
DO - 10.1016/j.canlet.2020.12.015
M3 - Article
C2 - 33326840
AN - SCOPUS:85098139209
VL - 500
SP - 182
EP - 193
JO - Cancer Letters
JF - Cancer Letters
SN - 0304-3835
ER -