Trabectedin overcomes doxorubicin-resistance, counteracts tumor-immunosuppressive reprogramming of monocytes and decreases xenograft growth in Hodgkin lymphoma.

ABSTRACT

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-ß, 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.