Notch1 signaling in melanoma cells promoted tumor-induced immunosuppression via upregulation of TGF-β1.
Notch1 signaling in melanoma cells promoted tumor-induced immunosuppression via upregulation of TGF-β1.
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黑色素瘤细胞中的 Notch1 信号通过上调 TGF-β1 促进肿瘤诱导的免疫抑制
DOI：
10.1186/s13046-017-0664-4
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发表时间：
2018-01-04
期刊：
影响因子：
--
通讯作者：
Kang S
中科院分区：
文献类型：
--
作者：
Yang Z;Qi Y;Lai N;Zhang J;Chen Z;Liu M;Zhang W;Luo R;Kang S
Notch家族受体在多种细胞类型的发育、分化和功能调控中发挥重要作用。本研究的目的是探讨Notch1信号在黑色素瘤细胞诱导的免疫抑制中的作用。用含小鼠Notch1基因或Notch1 shRNA的慢病毒转染黑色素瘤细胞系B16细胞，生成高表达或低表达Notch1的B16细胞系。在免疫正常和免疫缺陷小鼠B16黑色素瘤模型中，综合评价Notch1在抗肿瘤免疫应答中的作用。流式细胞术检测肿瘤dln和脾脏中CD3+CD8+细胞毒性T细胞、CD49b+NK细胞、CD4+CD25+FoxP3+ Tregs和Gr1+CD11b+ MDSCs的比例。B16细胞与CD8+ T细胞共培养后，采用CCK8法、CFSE稀释法和释铬法检测Notch1对T细胞增殖和活化的影响。RT-PCR和ELISA分别检测免疫抑制因子TGF-β1、VEGF、IL-10和IFN-γ mRNA表达和上清分泌。在免疫正常小鼠中，B16黑色素瘤细胞中Notch1的下调或过表达分别抑制或促进肿瘤生长。Notch1在B16黑色素瘤细胞中的表达抑制了CD8+细胞毒性T淋巴细胞和NK细胞的浸润，减少了肿瘤组织中IFN-γ的释放。它还能增强B16细胞介导的T细胞增殖和活化的抑制作用，上调CD4+和CD8+ T细胞上PD-1的表达。肿瘤微环境中CD4+CD25+FoxP3+ Tregs和Gr1+CD11b+MDSCs的比例显著升高，这些都与TGF-β1的上调有关。这些发现提示B16黑色素瘤细胞Notch1信号可能通过上调TGF-β1抑制抗肿瘤免疫。
The receptors of Notch family play an important role in controlling the development, differentiation, and function of multiple cell types. The aim of this study is to investigate the role of Notch1 signaling upon immune suppression induced by melanoma cells. Melanoma cell line B16 cells were transfected by lentivirus containing mouse Notch1 gene or Notch1 shRNA to generate B16 cell line that highly or lowly expressed Notch1. Notch1 in anti-tumor immune response was comprehensively appraised in murine B16 melanoma tumor model in immunocompetent and immunodeficient mice. The ratios of CD3+CD8+ cytotoxic T cells, CD49b+NK cells, CD4+CD25+FoxP3+ Tregs and Gr1+CD11b+ MDSCs in tumor-DLN or spleen were examined by flow cytometry. After the co-culture of B16 cells and CD8+ T cells, the effects of Notch1 on the proliferation and activation of T cells were assessed by CCK8 assay, CFSE dilution and Chromium-release test. The mRNA expression and supernatant secretion of immunosuppressive cytokines, TGF-β1, VEGF, IL-10 and IFN-γ were measured by RT-PCR and ELISA, respectively. Downregulation or overexpression of Notch1 in B16 melanoma cells inhibited or promoted tumor growth in immunocompetent mice, respectively. Notch1 expression in B16 melanoma cells inhibited the infiltration of CD8+ cytotoxic T lymphocytes and NK cells and reduced IFN-γ release in tumor tissue. It could also enhance B16 cell-mediated inhibition of T cell proliferation and activation, and upregulate PD-1 expression on CD4+ and CD8+ T cells. The percentage of CD4+CD25+FoxP3+ Tregs and Gr1+CD11b+MDSCs were significantly increased in tumor microenvironment, and all these were attributed to the upregulation of TGF-β1. These findings suggested that Notch1 signaling in B16 melanoma cells might inhibit antitumor immunity by upregulation of TGF-β1.
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DOI：
10.1038/nrclinonc.2011.116
发表时间：
2011-08-02
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Rosenberg SA
通讯作者：
Rosenberg SA
影响因子：
11.2
作者：
Ohnuki H;Jiang K;Wang D;Salvucci O;Kwak H;Sánchez-Martín D;Maric D;Tosato G
通讯作者：
Tosato G
影响因子：
0.2
作者：
Radosavljevic, Gordana D.;Jovanovic, Ivan P.;Arsenijevic, Nebojsa N.
通讯作者：
Arsenijevic, Nebojsa N.
影响因子：
11.2
作者：
Liu, ZJ;Xiao, M;Herlyn, M
通讯作者：
Herlyn, M
影响因子：
50.3
作者：
Wieland, Elfriede;Rodriguez-Vita, Juan;Fischer, Andreas
通讯作者：
Fischer, Andreas