IL-27 induces the expression of IDO and PD-L1 in human cancer cells.
IL-27 induces the expression of IDO and PD-L1 in human cancer cells.
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DOI：
10.18632/oncotarget.6530
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发表时间：
2015-12-22
期刊：
影响因子：
--
通讯作者：
Ferrini S
中科院分区：
文献类型：
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作者：
Carbotti G;Barisione G;Airoldi I;Mezzanzanica D;Bagnoli M;Ferrero S;Petretto A;Fabbi M;Ferrini S
IL-27是由巨噬细胞和树突状细胞产生的IL-12家族的成员。IL-27抑制不同癌症的生长和侵袭性，因此代表潜在的抗肿瘤剂。相反，它可能在不同的生物系统中发挥免疫调节作用。我们报道了IL-27诱导IL-18抑制剂IL-18 BP在人上皮性卵巢癌（EOC）细胞中的表达，从而潜在地限制免疫应答。在这里，我们测试了IL-27是否可以调节参与EOC进展的其他免疫调节分子，包括吲哚胺2，3-双加氧酶（IDO）和程序性死亡配体（PD-L）1。IDO和PD-L1在体外EOC细胞中不组成性表达，但IL-27通过STAT 1和STAT 3酪氨酸磷酸化增加其表达。不同的是，从EOC腹水中分离的细胞显示STAT 1和STAT 3的组成性激活以及IDO表达。这些发现，连同IL-27在EOC腹水和组织中的散在白细胞中的表达，表明IL-27在EOC的免疫调节网络中的潜在作用。此外，IL-27诱导单核细胞和人PC 3前列腺和A549肺癌细胞中的IDO或PD-L1表达。肿瘤免疫学中的当前范例是肿瘤细胞可由于由T细胞分泌的IFN-γ介导的“适应性抗性”而逃避免疫控制，所述IFN-γ诱导肿瘤细胞中的PD-Ll和IDO表达。我们目前的数据表明，IL-27也具有类似的活性，并表明IL-27作为抗癌剂的治疗用途在某些肿瘤中可能具有双重作用。
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.