title: 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.
authors.affiliation: Department of Immunology and Inflammation, IRCCS-Humanitas Clinical and Research Center, 20089 Rozzano, Milano, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Liguori
authors.affiliation: Department of Immunology and Inflammation, IRCCS-Humanitas Clinical and Research Center, 20089 Rozzano, Milano, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Buracchi
authors.affiliation: Department of Immunology and Inflammation, IRCCS-Humanitas Clinical and Research Center, 20089 Rozzano, Milano, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Pasqualini
authors.affiliation: Department of Immunology and Inflammation, IRCCS-Humanitas Clinical and Research Center, 20089 Rozzano, Milano, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bergomas
authors.affiliation: Department of Immunology and Inflammation, IRCCS-Humanitas Clinical and Research Center, 20089 Rozzano, Milano, Italy.
authors.forename: Samantha
authors.initials: S
authors.lastname: Pesce
authors.affiliation: Department of Immunology and Inflammation, IRCCS-Humanitas Clinical and Research Center, 20089 Rozzano, Milano, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Sironi
authors.affiliation: Department of Immunology and Inflammation, IRCCS-Humanitas Clinical and Research Center, 20089 Rozzano, Milano, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Grizzi
authors.affiliation: Department of Immunology and Inflammation, IRCCS-Humanitas Clinical and Research Center, 20089 Rozzano, Milano, Italy.|Humanitas University, 20089 Rozzano, Milano, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Mantovani
authors.affiliation: Department of Immunology and Inflammation, IRCCS-Humanitas Clinical and Research Center, 20089 Rozzano, Milano, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Belgiovine
authors.affiliation: Department of Immunology and Inflammation, IRCCS-Humanitas Clinical and Research Center, 20089 Rozzano, Milano, Italy.|Humanitas University, 20089 Rozzano, Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Allavena
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy / Q000379:methods; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology / Q000627:therapeutic use; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand
keywords: apoptosis; targeting macrophages; tumor-associated macrophages; TRAIL; TRAIL receptors