Characterization of the in vivo immune network of IDO, tryptophan metabolism, PD-L1, and CTLA-4 in circulating immune cells in melanoma
Characterization of the in vivo immune network of IDO, tryptophan metabolism, PD-L1, and CTLA-4 in circulating immune cells in melanoma
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DOI：
10.4161/2162402x.2014.982382
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发表时间：
2015-03-01
期刊：
影响因子：
7.2
通讯作者：
Brochez, L.
中科院分区：
文献类型：
--
作者：
Chevolet, I.;Speeckaert, R.;Brochez, L.
在黑色素瘤中，肿瘤细胞诱导的免疫抑制和炎性抗肿瘤反应都可以诱导肿瘤微环境中的反调节机制如吲哚胺2，3-双加氧酶（IDO）、程序性死亡配体1（PD-L1）和CTLA-4（+）调节性T细胞（TCL 1）的上调。尽管这些免疫抑制介质是免疫治疗的靶点，但缺乏研究它们在外周血中的表达。因此，我们对I-IV期黑素瘤患者的PBMC进行流式细胞术。在浆细胞样树突状细胞（pDC）和单核细胞骨髓源性抑制细胞（mMDSC）中检测到IDO表达，并且在晚期疾病阶段增加（p = 0.027）。色氨酸分解证实了IDO的功能活性，并与PD-L1+细胞毒性T细胞增加（p = 0.009）、相对淋巴细胞减少症（p = 0.036）和较高的mDC/pDC比值（p = 0.002）相关。高水平的循环PD-L1+细胞毒性T细胞与通过Tclad（p = 0.005）和MDSC水平（p = 0.033）增加的CTLA-4表达相关。这说明黑色素瘤中的反调节免疫机制应被视为一个相互关联的信号网络。此外，TcB中增加的PD-L1+ T细胞和CTLA-4表达均赋予阴性预后，表明其体内相关性。值得注意的是，循环CTLA-4、IDO和pDC水平根据前哨淋巴结的先前侵袭而改变，并且前哨中的IDO表达与更多的IDO+ PBMC相关。我们得出结论，IDO，PD-L1和CTLA-4在黑色素瘤患者外周血中的表达是密切相关的，与晚期疾病和阴性结果相关，与疾病分期无关。因此，靶向这些标志物中的几种的组合治疗可能发挥协同反应。
In melanoma, both the induction of immunosuppression by tumor cells and the inflammatory antitumor response can induce an upregulation of counter-regulatory mechanisms such as indoleamine 2,3-dioxygenase (IDO), programmed death-ligand 1 (PD-L1) and CTLA-4(+) regulatory T-cells (Tregs) in the tumor microenvironment. Even though these immunosuppressive mediators are targets for immunotherapy, research investigating their expression in the peripheral blood is lacking. We therefore, performed flow cytometry on PBMCs of stage I-IV melanoma patients. IDO expression was detected in plasmacytoid dendritic cells (pDC) and monocytic myeloid-derived suppressor cells (mMDSC), and increased in advanced disease stage (p = 0.027). Tryptophan breakdown confirmed the functional activity of IDO and was linked with increased PD-L1+ cytotoxic T-cells (p = 0.009), relative lymphopenia (p = 0.036), and a higher mDC/pDC ratio (p = 0.002). High levels of circulating PD-L1+ cytotoxic T-cells were associated with increased CTLA-4 expression by Tregs (p = 0.005) and MDSC levels (p = 0.033). This illustrates that counter-regulatory immune mechanisms in melanoma should be considered as one interrelated signaling network. Moreover, both increased PD-L1+ T-cells and CTLA-4 expression in Tregs conferred a negative prognosis, indicating their in vivo relevance. Remarkably, circulating CTLA-4, IDO, and pDC levels were altered according to prior invasion of the sentinel lymph node and IDO expression in the sentinel was associated with more IDO+ PBMCs. We conclude that the expression of IDO, PD-L1, and CTLA-4 in the peripheral blood of melanoma patients is strongly interconnected, associated with advanced disease and negative outcome, independent of disease stage. Combination treatments targeting several of these markers are therefore likely to exert a synergistic response.