Petretto Andrea, Carbotti Grazia, Inglese Elvira, Lavarello Chiara, Pistillo Maria Pia, Rigo Valentina, Croce Michela, Longo Luca, Martini Stefania, Vacca Paola, Ferrini Silvano, Fabbi Marina
Core Facilities-Proteomics Laboratory, Istituto Giannina Gaslini, Genoa, Italy.
Department of Integrated Oncological Therapies, IRCCS AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
Oncotarget. 2016 Nov 8;7(45):72518-72536. doi: 10.18632/oncotarget.12235.
IL-27, a member of the IL-12-family of cytokines, has shown anti-tumor activity in several pre-clinical models due to anti-proliferative, anti-angiogenic and immune-enhancing effects. On the other hand, IL-27 demonstrated immune regulatory activities and inhibition of auto-immunity in mouse models. Also, we reported that IL-27, similar to IFN-γ, induces the expression of IL-18BP, IDO and PD-L1 immune regulatory molecules in human cancer cells. Here, a proteomic analysis reveals that IL-27 and IFN-γ display a broad overlap of functions on human ovarian cancer cells. Indeed, among 990 proteins modulated by either cytokine treatment in SKOV3 cells, 814 showed a concordant modulation by both cytokines, while a smaller number (176) were differentially modulated. The most up-regulated proteins were common to both IFN-γ and IL-27. In addition, functional analysis of IL-27-regulated protein networks highlighted pathways of interferon signaling and regulation, antigen presentation, protection from natural killer cell-mediated cytotoxicity, regulation of protein polyubiquitination and proteasome, aminoacid catabolism and regulation of viral protein levels.Importantly, we found that IL-27 induced HLA class I molecule expression in human cancer cells of different histotypes, including tumor cells showing very low expression. IL-27 failed only in a cancer cell line bearing a homozygous deletion in the B2M gene. Altogether, these data point out to a broad set of activities shared by IL-27 and IFN-γ, which are dependent on the common activation of the STAT1 pathway. These data add further explanation to the anti-tumor activity of IL-27 and also to its dual role in immune regulation.
白细胞介素-27（IL-27）是细胞因子白细胞介素-12家族的成员之一，因其具有抗增殖、抗血管生成和免疫增强作用，在多种临床前模型中显示出抗肿瘤活性。另一方面，IL-27在小鼠模型中表现出免疫调节活性并抑制自身免疫。此外，我们报道过，IL-27与干扰素-γ（IFN-γ）类似，可诱导人癌细胞中白细胞介素-18结合蛋白（IL-18BP）、吲哚胺2,3-双加氧酶（IDO）和程序性死亡受体配体1（PD-L1）等免疫调节分子的表达。在此，蛋白质组学分析显示，IL-27和IFN-γ在人卵巢癌细胞上具有广泛的功能重叠。事实上，在SKOV3细胞中，经任何一种细胞因子处理后被调节的990种蛋白质中，有814种受到两种细胞因子的一致调节，而受差异调节的蛋白质数量较少（176种）。上调幅度最大的蛋白质是IFN-γ和IL-27共有的。此外，对IL-27调节的蛋白质网络进行功能分析，突出了干扰素信号传导与调节、抗原呈递、抵御自然杀伤细胞介导的细胞毒性、蛋白质多聚泛素化和蛋白酶体调节、氨基酸分解代谢以及病毒蛋白水平调节等途径。重要的是，我们发现IL-27可诱导不同组织类型的人癌细胞中I类人类白细胞抗原（HLA）分子的表达，包括那些表达水平极低的肿瘤细胞。只有在B2M基因发生纯合缺失的癌细胞系中，IL-27才无法发挥作用。总而言之，这些数据表明IL-27和IFN-γ具有广泛的共同活性，这依赖于信号转导和转录激活因子1（STAT1）途径的共同激活。这些数据进一步解释了IL-27的抗肿瘤活性及其在免疫调节中的双重作用。
