Synergistic effects of IL-4 and TNFα on the induction of B7-H1 in renal cell carcinoma cells inhibiting allogeneic T cell proliferation.
Synergistic effects of IL-4 and TNFα on the induction of B7-H1 in renal cell carcinoma cells inhibiting allogeneic T cell proliferation.
复制标题
DOI：
10.1186/1479-5876-12-151
复制
发表时间：
2014-05-30
影响因子：
7.4
通讯作者：
Seliger B
中科院分区：
文献类型：
--
作者：
Quandt D;Jasinski-Bergner S;Müller U;Schulze B;Seliger B
B7-H分子对T细胞/肿瘤通讯的重要性及其对肾细胞癌（RCC）进展和预后的影响最近已被描述。RCC的细胞因子治疗早期已被证明在临床前环境中是有益的，但其临床实施尚未被证明是有效的。这可能是部分解释的细胞因子治疗后，在本研究中详细研究的肿瘤细胞的细胞变化，但不完整的图片。RCC肿瘤细胞系用不同细胞因子单独或组合处理。通过qPCR和流式细胞术分析RCC细胞中细胞因子受体信号传导组分和B7-H分子的组成型和/或姜黄素诱导的表达。克隆了含有B7-H1启动子的mcherry报告基因构建体，并在转染后测定了其活性。将细胞因子预处理的肿瘤细胞与来自健康供体的同种异体CD 8 + T细胞共培养，并测定T细胞增殖以及细胞因子分泌。在人肾细胞癌细胞系上发现了异质的但组成型的B7-H1、-H2、-H3和H4表达。IL-4和TNFα处理导致RCC细胞中B7-H1的强烈协同诱导，而B7-H2仅被TNFα增加。相反，B7-H3和B7-H4的表达没有被这些细胞因子改变。用TNFα和IL-4处理RCC细胞伴随着NF-κB、IκB和STAT 6等信号分子的激活。在IL-4和TNFα存在下，通过B7-H1启动子活性增加确定，姜黄素介导的B7-H1上调是由于转录控制。尽管HLA I类和LFA-1也增加了，但苦参碱介导的B7-H1上调更明显，并导致同种异体特异性CD 8 + T细胞增殖的抑制。因此，可以由肿瘤微环境的免疫细胞释放的IL-4和TNFα能够控制RCC中的B7-H1表达，从而改变T细胞应答。这些数据对于理解肿瘤细胞与由许多不同的可溶性和膜结合介体协调的免疫细胞的复杂相互作用以及针对B7-H1的检查点抗体的实施是重要的。
The importance of B7-H molecules for the T cell/tumor communication and its impact on renal cell carcinoma (RCC) progression and prognosis has been recently described. Cytokine treatment of RCC has earlier been shown to be beneficial in preclinical settings, but its clinical implementation has not proven to be as effective. This might be partially explained by the yet incomplete picture of cellular alterations in tumor cells upon cytokine treatment investigated in detail in this study. RCC tumor cell lines were treated with different cytokines alone or in combination. The constitutive and/or cytokine-induced expression of cytokine receptors signaling components and B7-H molecules in RCC cells were analysed by qPCR and flow cytometry. A mcherry reporter gene construct containing B7-H1 promoter was cloned and its activity was determined upon transfection in cytokine-stimulated cells. Cytokine pretreated tumor cells were co-cultured with allogeneic CD8+ T cells from healthy donors and T cell proliferation as well as cytokine secretion was determined. A heterogeneous, but constitutive B7-H1,-H2,-H3 and H4 expression was found on human RCC cell lines. IL-4 and TNFα treatment led to strong synergistic induction of B7-H1 in RCC cells, whereas B7-H2 was only increased by TNFα. In contrast, B7-H3 and B7-H4 expression were not altered by these cytokines. Treatment of RCC cells with TNFα and IL-4 was accompanied by an activation of signaling molecules like NF-κB, IκB and STAT6. The cytokine-mediated up-regulation of B7-H1 was due to transcriptional control as determined by an increased B7-H1 promoter activity in the presence of IL-4 and TNFα. Despite HLA class I and LFA-1 were also increased, the cytokine-mediated up-regulation of B7-H1 was more pronounced and caused an inhibition of allospecifc CD8+ T cell proliferation. Thus, IL-4 and TNFα, which could be released by immune cells of the tumor microenvironment, are able to control the B7-H1 expression in RCC thereby altering T cell responses. These data are of importance for understanding the complex interplay of tumor cells with immune cells orchestrated by a number of different soluble and membrane bound mediators and for the implementation of check point antibodies directed against B7-H1.
登录
查看更多内容
影响因子：
20.3
作者：
Kondo, Asaka;Yamashita, Taishi;Ogata, Kiyoyuki
通讯作者：
Ogata, Kiyoyuki
影响因子：
30.5
作者：
Latchman, Y;Wood, CR;Freeman, GJ
通讯作者：
Freeman, GJ
影响因子：
3.9
作者：
MARGOLIN, K;ARONSON, FR;WEISS, GR
通讯作者：
WEISS, GR
影响因子：
32.4
作者：
Butte, Manish J.;Keir, Mary E.;Freeman, Gordon J.
通讯作者：
Freeman, Gordon J.
影响因子：
4.4
作者：
Mazanet, MM;Hughes, CCW
通讯作者：
Hughes, CCW