Department of Molecular Oncology, CRO Aviano National Cancer Institute, Aviano, PN, Italy
*CB and NC contributed equally.
The adverse prognostic impact of the immunosuppressive tumor-associated macrophages (TAMs) in classical Hodgkin Lymphoma (cHL) is now well established and the depletion of TAMs is a key mechanism of the antitumor efficacy of trabectedin, a DNA damaging agent of marin origin.
Our studies demonstrated that trabectedin: had a potent antitumor activity in cHL cells, with IC50 ranging from 0.17 to 0.5 nM; induced DNA damage resulting in G2/M cell cycle arrest; induced necroptosis and increased the generation of reactive oxygen species. Trabectedin was active also in the presence of mesenchymal stromal cells (MSCs), which have been shown to play a role in chemotherapy resistance.
Treatment of cHL cells with subtoxic concentrations of trabectedin decreased: NF-kB activity; CCL5, CCL17/TARC, IL-6, IL-13, M-CSF and TGF-β secretion; the capability of cHL-conditioned medium (CM) to induce the migration of monocytes, MSCs, and lymphocytes; the reprogramming/tumor-education of monocytes (E-monocytes) towards immunosuppressive macrophages, characterized by increased IDO and PD-L1 expression, the secretion of IL-10, TGF-β, and TARC, and the inhibition of the proliferation of activated lymphocytes.
Trabectedin exerted a moderate synergistic activity with gemcitabine, but not with cisplatin, doxorubicin or vinorelbine. The combination with the CCR5-antagonist Maraviroc, found to increase cell killing mediated by DNA-damaging chemotherapeutic agents as doxorubicin, enhanced the cytotoxic effects of trabectedin in cHL, especially in L-540 cells, decreasing the IC50 of trabectedin-mediated cell killing by up to 2-fold.
In vivo, trabectedin (50 μg/Kg) led to a more than 40% tumor growth reduction of L-540-derived tumor xenograft and inhibited monocytes tumor infiltration, without weight loss.
In conclusion, since the present challenges are to find new drugs or less toxic drug combinations, as well as counteract the formation of an immunosuppressive tumor microenvironment, this study offers a preclinical rationale for the use of trabectedin in the treatment of refractory/relapsed cHL.