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.
Highlights
Immune-regulatory mechanisms play a crucial role in cancer progression, as they limit the anti-tumor immune response [1, 2]
If human A2774 Epithelial Ovarian Cancer (EOC) cells are implanted in SCID mice, IDO expression is observed in the engrafted tumor cells (Figure S1)
As EOC cell lines are responsive to IL-27 [17], we asked whether IDO expression may be modulated by IL-27 in a panel of 6 cell lines representative of different sub-types of this cancer (Table S1) [49, 50]
Summary
Immune-regulatory mechanisms play a crucial role in cancer progression, as they limit the anti-tumor immune response [1, 2]. The enzyme Indoleamine 2,3-dioxygenase (IDO) is expressed in neoplastic cells and tumor-associated leukocytes or dendritic cells, and its expression correlates with a shorter survival, in different cancers [4]. Several experimental models and clinical studies in cancer patients indicate that targeting of immuneregulatory mechanisms may restore the immune response and mediate therapeutic effects. Immunewww.impactjournals.com/oncotarget enhancing monoclonal antibodies (mAbs) that target immune check-points such as anti-PD-1 and anti-PD-L1 have shown clinical benefit in different cancers [1, 2, 6, 7]. High tumor-infiltrating T cell counts have a positive impact on the clinical course of EOC [12,13,14,15]
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