Lung adenocarcinoma-intrinsic GBE1 signaling inhibits anti-tumor immunity
Lung adenocarcinoma-intrinsic GBE1 signaling inhibits anti-tumor immunity
复制标题
肺腺癌固有的 GBE1 信号传导抑制抗肿瘤免疫
DOI：
10.1186/s12943-019-1027-x
复制
发表时间：
2019-06-20
期刊：
影响因子：
37.3
通讯作者：
Zhang, Yi
中科院分区：
文献类型：
--
作者：
Li, Lifeng;Yang, Li;Zhang, Yi
研究背景糖原代谢的改变是肿瘤细胞适应肿瘤微环境的一个重要特征。我们之前的研究表明，糖原分支酶（GBE 1）位于缺氧条件下肺癌细胞中HIF 1通路的下游。在本研究中，我们研究了GBE 1是否参与肺腺癌（LUAD）肿瘤微环境的免疫调节。方法我们使用RNA测序分析和多重检测来确定GBE 1敲低细胞的变化。结果GBE 1基因敲减后A549细胞中趋化因子CCL 5和CXCL 10的表达增加。LUAD中CD 8表达与CCL 5、CXCL 10表达呈正相关。来自GBE 1敲减细胞的上清液增加了CD 8 +T淋巴细胞的募集。然而，CCL 5或CXCL 10的中和抗体显著抑制由shGBE 1细胞上清液诱导的细胞迁移。STING/IFN-I途径介导GBE 1敲低对CCL 5和CXCL 10上调的作用。此外，与对照细胞相比，shGBE 1 A549细胞中的PD-L1显著增加。此外，在LUAD肿瘤组织中，观察到PD-L1和GBE 1之间存在负相关。结论GBE 1阻断剂通过IFN-1/STING信号通路促进LUAD细胞分泌CCL 5和CXCL 10，募集CD 8 +T淋巴细胞进入肿瘤微环境，同时上调PD-L1表达，这表明GBE 1可能是通过LUAD中的癌症免疫疗法实现肿瘤消退的有希望的靶点。
BackgroundChanges in glycogen metabolism is an essential feature among the various metabolic adaptations used by cancer cells to adjust to the conditions imposed by the tumor microenvironment. Our previous study showed that glycogen branching enzyme (GBE1) is downstream of the HIF1 pathway in hypoxia-conditioned lung cancer cells. In the present study, we investigated whether GBE1 is involved in the immune regulation of the tumor microenvironment in lung adenocarcinoma (LUAD).MethodsWe used RNA-sequencing analysis and the multiplex assay to determine changes in GBE1 knockdown cells. The role of GBE1 in LUAD was evaluated both in vitro and in vivo.ResultsGBE1 knockdown increased the expression of chemokines CCL5 and CXCL10 in A549 cells. CD8 expression correlated positively with CCL5 and CXCL10 expression in LUAD. The supernatants from the GBE1 knockdown cells increased recruitment of CD8+T lymphocytes. However, the neutralizing antibodies of CCL5 or CXCL10 significantly inhibited cell migration induced by shGBE1 cell supernatants. STING/IFN-I pathway mediated the effect of GBE1 knockdown for CCL5 and CXCL10 upregulation. Moreover, PD-L1 increased significantly in shGBE1 A549 cells compared to those in control cells. Additionally, in LUAD tumor tissues, a negative link between PD-L1 and GBE1 was observed. Lastly, blockade of GBE1 signaling combined with anti-PD-L1 antibody significantly inhibited tumor growth in vivo.ConclusionsGBE1 blockade promotes the secretion of CCL5 and CXCL10 to recruit CD8+T lymphocytes to the tumor microenvironment via the IFN-I/STING signaling pathway, accompanied by upregulation of PD-L1 in LUAD cells, suggesting that GBE1 could be a promising target for achieving tumor regression through cancer immunotherapy in LUAD.