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

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.

Significantly mutated genes and regulatory pathways in SCLC—a meta-analysis

“…It is known to play a critical role in regulating the interaction between innate and adaptive antitumor immunity and has been shown to possess the ability to inhibit tumor growth and invasiveness [36]. There is increasing interest in cancer immunotherapy and modulation of the patients’ immune system to target cancer cells.…”

Proteomic analysis uncovers common effects of IFN-γ and IL-27 on the HLA class I antigen presentation machinery in human cancer cells

“…Perhaps more importantly, it induced the expression of the immune-suppressive molecules IDO and PD-L1, in human cancer cells, through the activation of STAT1 or STAT3 pathways, respectively [23]. It is noteworthy that both IL-27 and IFN-γ induce IL-18BP, PD-L1, and IDO, suggesting that these cytokines may have other, yet unknown, common effects.…”

Stat3 inhibitor abrogates the expression of PD-1 ligands on lymphoma cell lines

“…21 In ovarian cancer cells, PD-L1 expression was reported to be up-regulated by IL-27 and IFN-γ via activation of Stat1 and Stat3. 22 However, there have been few studies related to PD-L1/2 expression in aggressive lymphomas. In the present study, we demonstrated that PD-L1/2 expression was significantly reduced by a Stat3 inhibitor, and this finding might be the first report to show a relationship between PD-L1/2 expression and Stat3 in lymphoma.…”