IL-27 induces the expression of IDO and PD-L1 in human cancer cells

// Grazia Carbotti 1 , Gaia Barisione 1 , Irma Airoldi 2 , Delia Mezzanzanica 3 , Marina Bagnoli 3 , Simone Ferrero 4 , Andrea Petretto 5 , Marina Fabbi 1 and Silvano Ferrini 1 1 Department of Integrated Oncological Therapies, IRCCS AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy 2 Laboratory of Oncology, Istituto Giannina Gaslini, Genoa, Italy 3 Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 4 Department of Surgery, Unit of Obstetrics and Gynaecology, IRCCS AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, and DINOGMI, University of Genoa Genoa, Italy 5 Core Facilities, Istituto Giannina Gaslini, Genoa, Italy Correspondence to: Silvano Ferrini, email: // Marina Fabbi, email: // Keywords : IL-27, IDO, PD-L1, STAT, Immunology and Microbiology Section, Immune response, Immunity Received : July 08, 2015 Accepted : November 30, 2015 Published : December 09, 2015 Abstract IL-27 is a member of the IL-12 family that is produced by macrophages and dendritic cells. IL-27 inhibits the growth and invasiveness of different cancers and therefore represents a potential anti-tumor agent. By contrast, it may exert immune-regulatory properties in different biological systems. We reported that IL-27 induces the expression of the IL-18 inhibitor IL-18BP, in human Epithelial Ovarian Cancer (EOC) cells, thus potentially limiting the immune response. Here, we tested whether IL-27 may modulate other immune-regulatory molecules involved in EOC progression, including Indoleamine 2,3-dioxygenase (IDO) and Programmed Death-Ligand (PD-L)1. IDO and PD-L1 were not constitutively expressed by EOC cells in vitro , but IL-27 increased their expression through STAT1 and STAT3 tyrosine phosphorylation. Differently, cells isolated from EOC ascites showed constitutive activation of STAT1 and STAT3 and IDO expression. These findings, together with the expression of IL-27 in scattered leukocytes in EOC ascites and tissues, suggest a potential role of IL-27 in immune-regulatory networks of EOC. In addition, IL-27 induced IDO or PD-L1 expression in monocytes and in human PC3 prostate and A549 lung cancer cells. A current paradigm in tumor immunology is that tumor cells may escape from immune control due to “adaptive resistance” mediated by T cell-secreted IFN-γ, which induces PD-L1 and IDO expression in tumor cells. Our present data indicate that also IL-27 has similar activities and suggest that the therapeutic use of IL-27 as anti-cancer agent may have dual effects, in some tumors.