Functional TRAIL receptors in monocytes and tumor-associated macrophages: A possible targeting pathway in the tumor microenvironment

Abstract

Despite the accepted dogma that TRAIL kills only tumor cells and spares normal ones, we show in this study that mononuclear phagocytes are susceptible to recombinant TRAIL via caspase-dependent apoptosis. Human resting monocytes and in vitro-differentiated macrophages expressed substantial levels of the functional TRAIL receptors (TRAIL-R1 and TRAIL-R2), while neutrophils and lymphocytes mostly expressed the non-signaling decoy receptor (TRAIL-R3). Accordingly, exclusively monocytes and macrophages activated caspase-8 and underwent apoptosis upon recombinant TRAIL treatment. TRAIL-Rs were up-regulated by anti-inflammatory agents (IL-10, glucocorticoids) and by natural compounds (Apigenin, Quercetin, Palmitate) and their treatment resulted in increased TRAIL-induced apoptosis. In mice, the only signaling TRAIL-R (DR5) was preferentially expressed by blood monocytes rather than neutrophils or lymphocytes. In both mice and humans, Tumor-Associated Macrophages (TAM) expressed functional TRAIL-R, while resident macrophages in normal tissues did not. As a proof of principle, we treated mice bearing a murine TRAIL-resistant fibrosarcoma with recombinant TRAIL. We observed significant decrease of circulating monocytes and infiltrating TAM, as well as reduced tumor growth and lower metastasis formation. Overall, these findings demonstrate that human and murine monocytes/macrophages are, among leukocytes, uniquely susceptible to TRAIL-mediated killing. This differential susceptibility to TRAIL could be exploited to selectively target macrophages in tumors.

Lurbinectedin reduces tumour-associated macrophages and the inflammatory tumour microenvironment in preclinical models

“…Mechanistically, lurbinectedin activates caspase-8-dependent apoptosis in human monocytes within few hours and at low nanomolar concentrations. We previously demonstrated that the selectivity of trabectedin for the mononuclear phagocyte lineage relies on the fact that only monocytes and macrophages express appreciable levels of functional TRAIL-R, whereas neutrophils and T lymphocytes express high levels of the decoy non-signalling TRAIL-R3, and therefore are spared by the drug ( Germano et al , 2013 ; Liguori et al , 2016 ). In treated monocytes, trabectedin upregulates the transcription of TRAIL-R and this increase appears to be sufficient to trigger caspase-8 activation and apoptosis.…”

“…Monocytes were purified through density gradients, as described ( Liguori et al , 2016 ). Cells were treated with lurbinectedin or trabectedin (2.5–10 n M ) for different time points as indicated.…”

Progress in tumor-associated macrophage (TAM)-targeted therapeutics

“…In particular, trabectedin and its second generation lurbinectedin are effective at killing TAMs in addition to cancer cells [153][154]. Mechanistically, trabectedin interacts with tumor necrosis factor-related apoptosis inducing ligand receptor 2 (TRAIL-R2) on mononuclear phagocytes leading to receptor clustering and subsequent caspase-8 dependent activation of apoptosis [154][155]. Its selective toxicity in TAMs over neutrophils and lymphocytes has been attributed to higher expression of the receptor in conjunction with lower expression of non-signaling decoy TRAIL-R3.…”

Cancer Inflammation and Cytokines

“…Trabectedin is an European Medicines Evaluation Agency (EMEA)-approved natural product with antitumor activity (Germano et al 2010). Indeed, trabectedin activated the TRAIL-dependent apoptotic pathway selectively in monocytes, because of their low expression of TRAIL decoy receptors (Liguori et al 2016). In murine models and human sarcoma patients, trabectedin treatment resulted in a reduction of TAM infiltration and angiogenesis (Germano et al 2010), thus suggesting a promising role in TAM-targeted antitumor therapies.…”