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

Abstract

// Manuela Liguori 1 , Chiara Buracchi 1 , Fabio Pasqualini 1 , Francesca Bergomas 1 , Samantha Pesce 1 , Marina Sironi 1 , Fabio Grizzi 1 , Alberto Mantovani 1, 2 , Cristina Belgiovine 1, * , Paola Allavena 1, 2, * 1 Department of Immunology and Inflammation, IRCCS-Humanitas Clinical and Research Center, 20089 Rozzano, Milano, Italy 2 Humanitas University, 20089 Rozzano, Milano, Italy * These authors have contributed equally to this work Correspondence to: Cristina Belgiovine, email: cristina.belgiovine@humanitasresearch.it Paola Allavena, email: paola.allavena@humanitasresearch.it Keywords: TRAIL, TRAIL receptors, apoptosis, tumor-associated macrophages, targeting macrophages Received: February 17, 2016      Accepted: April 06, 2016      Published: May 13, 2016 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.