EGFR signaling suppresses type 1 cytokine-induced T-cell attracting chemokine secretion in head and neck cancer.
EGFR signaling suppresses type 1 cytokine-induced T-cell attracting chemokine secretion in head and neck cancer.
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DOI：
10.1371/journal.pone.0203402
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
van der Burg SH
中科院分区：
文献类型：
--
作者：
Ma W;Concha-Benavente F;Santegoets SJAM;Welters MJP;Ehsan I;Ferris RL;van der Burg SH
对抗肿瘤免疫的抗性可以通过在人类癌症中起作用的致癌途径（包括表皮生长因子受体（EGFR）途径）来促进。在这里，我们研究了头颈部鳞状细胞癌（HNSCC）中EGFR下游信号传导是否以及如何影响免疫细胞的吸引力。使用qPCR、ELISA和迁移实验，在体外分析HPV阴性和HPV阳性HNSCC细胞系的CCL 2、CCL 5、CXCL 9、CXCL 10、IL-6和IL-1β表达以及在不同条件下T细胞的吸引力，包括西妥昔单抗处理和IFNγ和TNFα刺激。使用化学抑制剂和siRNA转染的生化分析来查明潜在的机制。用IFNγ和TNFα刺激HNSCC细胞触发T细胞吸引趋化因子的产生，并需要c-RAF活化。在这种刺激过程中，用西妥昔单抗阻断EGFR增加了体外趋化因子的产生，并增强了T细胞的吸引力。从机制上讲，西妥昔单抗降低了MEK 1、ERK 1/2、AKT、mTOR、JNK、p38和ERK 5的磷酸化。EGFR信号传导的化学抑制显示出与MEK 1/2抑制剂PD 98059和JNK抑制剂SP 600125一致且显著的趋化因子产生，但与p38、PI 3 K或mTOR的抑制剂不一致。西妥昔单抗和MEK 1/2或JNK抑制剂的联合治疗诱导了最高的趋化因子表达。总之，EGFR的过表达导致多种下游信号传导途径的激活，所述多种下游信号传导途径同时起作用以抑制1型细胞因子刺激的趋化因子的产生，所述趋化因子是放大T细胞的吸引力所需的。
Resistance to antitumor immunity can be promoted by the oncogenic pathways operational in human cancers, including the epidermal growth factor receptor (EGFR) pathway. Here we studied if and how EGFR downstream signaling in head and neck squamous cell carcinoma (HNSCC) can affect the attraction of immune cells. HPV-negative and HPV-positive HNSCC cell lines were analyzed in vitro for CCL2, CCL5, CXCL9, CXCL10, IL-6 and IL-1β expression and the attraction of T cells under different conditions, including cetuximab treatment and stimulation with IFNγ and TNFα using qPCR, ELISA and migration experiments. Biochemical analyses with chemical inhibitors and siRNA transfection were used to pinpoint the underlying mechanisms. Stimulation of HNSCC cells with IFNγ and TNFα triggered the production of T-cell attracting chemokines and required c-RAF activation. Blocking of the EGFR with cetuximab during this stimulation increased chemokine production in vitro, and augmented the attraction of T cells. Mechanistically, cetuximab decreased the phosphorylation of MEK1, ERK1/2, AKT, mTOR, JNK, p38 and ERK5. Chemical inhibition of EGFR signaling showed a consistent and pronounced chemokine production with MEK1/2 inhibitor PD98059 and JNK inhibitor SP600125, but not with inhibitors of p38, PI3K or mTOR. Combination treatment with cetuximab and a MEK1/2 or JNK inhibitor induced the highest chemokine expression. In conclusion, overexpression of EGFR results in the activation of multiple downstream signaling pathways that act simultaneously to suppress type 1 cytokine stimulated production of chemokines required to amplify the attraction of T cells.
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影响因子：
4.4
作者：
Pastore, S;Mascia, F;Girolomoni, G
通讯作者：
Girolomoni, G
影响因子：
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通讯作者：
Hwu P
影响因子：
8.8
作者：
Balermpas, P;Michel, Y;Wagenblast, J;Seitz, O;Weiss, C;Rodel, F;Rodel, C;Fokas, E
通讯作者：
Fokas, E
影响因子：
11.4
作者：
BELKA, C;WIEGMANN, K;BRACH, MA
通讯作者：
BRACH, MA
影响因子：
11.5
作者：
Badoual, C;Hans, S;Tartour, E
通讯作者：
Tartour, E