Department of Breast Oncoplastic Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Huan-Hu-Xi Road Ti-Yuan-Bei, Hexi District, Tianjin, 300060, China.
Tianjin Medical University, Ministry of Education, Tianjin, 300060, China.
Breast Cancer Res Treat. 2018 Sep;171(2):345-357. doi: 10.1007/s10549-018-4833-8. Epub 2018 May 29.
Syntenin1/SDCBP (syndecan binding protein), also known as melanoma differentiation associated gene-9 (MDA-9), is a PDZ domain-containing molecule, which was initially identified as a key oncogene in melanoma. However, the role of syntenin1 in triple-negative breast cancer (TNBC), especially in suppression of antitumour immune response, remains unknown.
One hundred TNBC tissues were obtained after radical resection and used for analysis. High syntenin1 expression was associated with increased tumour size (r = 0.421, P < 0.001), presence of lymph node metastasis (r = 0.221, P = 0.044) and poor overall survival (P = 0.01) and recurrence-free survival (P = 0.007). Syntenin1 overexpression significantly promoted 4T1 tumour growth and lung metastasis in BALB/c mice by affecting CD8 T cells. Western blot and flow cytometry analyses demonstrated that syntenin1 induced CD8 T cell apoptosis in vitro and in vivo through upregulating PD-L1. Western blot demonstrated that syntenin1 upregulated PD-L1 expression by inducing Tyr705 stat3 phosphorylation, which was further confirmed by stat3 inhibition study. The correlation between syntenin1 and PD-L1 was further confirmed using tumour tissues derived from patients with TNBC (r = 0.509, P < 0.001). Efficacy studies indicated that 4T1-scramble tumour benefitted from anti-PD-L1 therapy (P < 0.001); however, 4T1-syntenin1-KD demonstrated no response to anti-PD-L1 treatment (P = 0.076).
Syntenin1 exhibits a profound function in mediating T cells apoptosis by upregulating PD-L1 and thus could be used as a prognostic biomarker of TNBC. Tumoural syntenin1 expression corelated with anti-PD-L1 treatment efficacy. Targeting syntenin1-mediated T-cell suppression could be a potential strategy for improving the prognosis of patients with TNBC.
Syntenin1/SDCBP（连接蛋白结合蛋白），也称为黑色素瘤分化相关基因-9（MDA-9），是一种 PDZ 结构域含有分子，最初被鉴定为黑色素瘤中的关键癌基因。然而，syntenin1 在三阴性乳腺癌（TNBC）中的作用，特别是在抑制抗肿瘤免疫反应方面，仍然未知。
对 100 例根治性切除后的 TNBC 组织进行分析。高 syntenin1 表达与肿瘤体积增大（r=0.421，P<0.001）、淋巴结转移（r=0.221，P=0.044）和不良总生存（P=0.01）和无复发生存（P=0.007）相关。Syntenin1 过表达通过影响 CD8 T 细胞显著促进 BALB/c 小鼠 4T1 肿瘤生长和肺转移。Western blot 和流式细胞术分析表明，syntenin1 通过上调 PD-L1 诱导 CD8 T 细胞凋亡。Western blot 表明，syntenin1 通过诱导 Tyr705 stat3 磷酸化而上调 PD-L1 表达，这进一步通过 stat3 抑制研究得到证实。使用来自 TNBC 患者的肿瘤组织进一步证实了 syntenin1 与 PD-L1 之间的相关性（r=0.509，P<0.001）。疗效研究表明，4T1- scramble 肿瘤受益于抗 PD-L1 治疗（P<0.001）；然而，4T1-syntenin1-KD 对抗 PD-L1 治疗无反应（P=0.076）。
Syntenin1 通过上调 PD-L1 介导 T 细胞凋亡，在介导 T 细胞凋亡中具有深远的功能，因此可作为 TNBC 的预后生物标志物。肿瘤 syntenin1 表达与抗 PD-L1 治疗疗效相关。靶向 syntenin1 介导的 T 细胞抑制可能是改善 TNBC 患者预后的一种潜在策略。
