Role of Macrophage Targeting in the Antitumor Activity of Trabectedin
Menée à l'aide de quatre modèles murins, cette étude montre que le mécanisme d'action antitumorale de la trabectédine consiste à induire une apoptose dans les phagocytes mononucléés exclusivement
There is widespread interest in macrophages as a therapeutic target in cancer. Here, we demonstrate that trabectedin, a recently approved chemotherapeutic agent, induces rapid apoptosis exclusively in mononuclear phagocytes. In four mouse tumor models, trabectedin caused selective depletion of monocytes/macrophages in blood, spleens, and tumors, with an associated reduction of angiogenesis. By using trabectedin-resistant tumor cells and myeloid cell transfer or depletion experiments, we demonstrate that cytotoxicity on mononuclear phagocytes is a key component of its antitumor activity. Monocyte depletion, including tumor-associated macrophages, was observed in treated tumor patients. Trabectedin activates caspase-8-dependent apoptosis; selectivity for monocytes versus neutrophils and lymphocytes is due to differential expression of signaling and decoy TRAIL receptors. This unexpected property may be exploited in different therapeutic strategies. º Trabectedin is a recently approved antitumor agent of marine origin º Trabectedin activates caspase-8-dependent apoptosis exclusively in myelomonocytes º In vivo trabectedin reduces monocytes and TAM, and related angiogenesis º Depletion of TAM is a key component of the antitumor efficacy of trabectedin