Interferon Signaling Is Frequently Downregulated in Melanoma.
Interferon Signaling Is Frequently Downregulated in Melanoma.
复制标题
DOI：
10.3389/fimmu.2018.01414
复制
发表时间：
2018
影响因子：
7.3
通讯作者：
Rizos H
中科院分区：
文献类型：
--
作者：
Alavi S;Stewart AJ;Kefford RF;Lim SY;Shklovskaya E;Rizos H
阻断程序性细胞死亡蛋白 1/PD-L1 通路的免疫检查点抑制剂可显着提高晚期黑色素瘤患者的生存率。免疫疗法仅对 15-40% 的黑色素瘤患者有效，并且耐药性与抗原呈递和干扰素信号通路的缺陷有关。在这项研究中，我们检查了一大组未接触过免疫检查点抑制剂的黑色素瘤细胞中的干扰素-γ (IFNγ) 反应，这些细胞具有明确的遗传驱动因素。 BRAF 突变型 (n = 11)、NRAS 突变型 (n = 10)、BRAF/NRAS 野生型 (n = 10) 和 GNAQ/GNA11 突变型葡萄膜黑色素瘤 (UVM) (n = 8)。通过流式细胞术分析已建立的 IFNγ 下游靶点 PD-L1、PD-L2、HLA-A、-B 和 -C、HLA-DR 和神经生长因子受体 (NGFR) 的细胞表面表达。 HLA-A、-B、-C、HLA-DR、NGFR 和 PD-L2 的基础细胞表达水平可预测 IFNγ 刺激的水平，而 PD-L1 诱导与基础表达水平无关。所测试的黑色素瘤细胞系中，只有 13/39 (33%) 对 IFNγ 有反应，并有效诱导所有靶标，表明 IFNγ 信号传导的下调在黑色素瘤中很常见。此外，我们还发现了两种公认的免疫治疗耐药机制，即β-2-微球蛋白的丧失和干扰素γ受体1表达。我们还检查了黑色素瘤驱动癌基因对 IFNγ 信号传导的影响，我们的数据表明 UVM 对 IFNγ 的反应能力减弱，几个靶标的诱导表达较低，这与 UVM 对免疫疗法的令人失望的反应一致。我们的结果表明，黑色素瘤对 IFNγ 的反应是异质的，在未使用免疫检查点抑制剂的黑色素瘤中经常下调，并且可能预测对免疫治疗的反应。
Immune checkpoint inhibitors that block the programmed cell death protein 1/PD-L1 pathway have significantly improved the survival of patients with advanced melanoma. Immunotherapies are only effective in 15–40% of melanoma patients and resistance is associated with defects in antigen presentation and interferon signaling pathways. In this study, we examined interferon-γ (IFNγ) responses in a large panel of immune checkpoint inhibitor-naïve melanoma cells with defined genetic drivers; BRAF-mutant (n = 11), NRAS-mutant (n = 10), BRAF/NRAS wild type (n = 10), and GNAQ/GNA11-mutant uveal melanomas (UVMs) (n = 8). Cell surface expression of established IFNγ downstream targets PD-L1, PD-L2, HLA-A, -B, and -C, HLA-DR, and nerve growth factor receptor (NGFR) were analyzed by flow cytometry. Basal cellular expression levels of HLA-A, -B, -C, HLA-DR, NGFR, and PD-L2 predicted the levels of IFNγ-stimulation, whereas PD-L1 induction was independent of basal expression levels. Only 13/39 (33%) of the melanoma cell lines tested responded to IFNγ with potent induction of all targets, indicating that downregulation of IFNγ signaling is common in melanoma. In addition, we identified two well-recognized mechanisms of immunotherapy resistance, the loss of β-2-microglobulin and interferon gamma receptor 1 expression. We also examined the influence of melanoma driver oncogenes on IFNγ signaling and our data suggest that UVM have diminished capacity to respond to IFNγ, with lower induced expression of several targets, consistent with the disappointing response of UVM to immunotherapies. Our results demonstrate that melanoma responses to IFNγ are heterogeneous, frequently downregulated in immune checkpoint inhibitor-naïve melanoma and potentially predictive of response to immunotherapy.
登录
查看更多内容
影响因子：
64.8
作者：
Manguso RT;Pope HW;Zimmer MD;Brown FD;Yates KB;Miller BC;Collins NB;Bi K;LaFleur MW;Juneja VR;Weiss SA;Lo J;Fisher DE;Miao D;Van Allen E;Root DE;Sharpe AH;Doench JG;Haining WN
通讯作者：
Haining WN
影响因子：
64.5
作者：
Benci JL;Xu B;Qiu Y;Wu TJ;Dada H;Twyman-Saint Victor C;Cucolo L;Lee DSM;Pauken KE;Huang AC;Gangadhar TC;Amaravadi RK;Schuchter LM;Feldman MD;Ishwaran H;Vonderheide RH;Maity A;Wherry EJ;Minn AJ
通讯作者：
Minn AJ
DOI：
10.1084/jem.20160801
发表时间：
2017-04-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Juneja VR;McGuire KA;Manguso RT;LaFleur MW;Collins N;Haining WN;Freeman GJ;Sharpe AH
通讯作者：
Sharpe AH
影响因子：
12.3
作者：
Robinson MD;Oshlack A
通讯作者：
Oshlack A
影响因子：
14.9
作者：
Samarajiwa SA;Forster S;Auchettl K;Hertzog PJ
通讯作者：
Hertzog PJ