ASCL1 promotes tumor progression through cell-autonomous signaling and immune modulation in a subset of lung adenocarcinoma
ASCL1 promotes tumor progression through cell-autonomous signaling and immune modulation in a subset of lung adenocarcinoma
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DOI：
10.1016/j.canlet.2020.06.002
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发表时间：
2020-10-01
期刊：
影响因子：
9.7
通讯作者：
Saito, Akira
中科院分区：
文献类型：
--
作者：
Miyashita, Naoya;Horie, Masafumi;Saito, Akira
ASCL1是神经内分泌分化的主要调节因子，它定义了肺腺癌的一个亚群。然而，ASCL1在肺肿瘤发生中的作用机制及其与免疫微环境的关系尚不清楚。免疫组织化学显示ASCL1阳性肺腺癌的免疫状态。在此基础上，将ASCL1基因导入小鼠肺腺癌细胞系，并进行了比较RNA测序和分泌组分析。在同种异体原位移植模型中探讨了ASCL1在肿瘤发生中的作用。ASCL1阳性的肺腺癌显示CD8(+)、CD4(+)、CD20(+)和FOXP3(+)淋巴细胞和CD163(+)巨噬细胞的低渗透，表明免疫沙漠表型。异位ASCL1上调小鼠细胞周期蛋白转录水平，刺激细胞增殖，促进肿瘤生长。ASCL1抑制趋化因子的分泌，包括CCL20、CXCL2、CXCL10和CXCL16，表明对免疫细胞的运输有影响。ASCL1阳性的肺腺癌中CXCR3和CCR6的表达细胞丰度较低，与淋巴细胞的低浸润性相一致。结论：ASCL1不仅通过细胞自主信号转导，而且还通过调节趋化因子的产生和免疫反应来介导其促肿瘤作用。这些发现表明，ASCL1阳性肿瘤代表了一种临床相关的肺癌实体。
The master regulator of neuroendocrine differentiation, achaete-scute complex homolog 1 (ASCL1) defines a subgroup of lung adenocarcinoma. However, the mechanistic role of ASCL1 in lung tumorigenesis and its relation to the immune microenvironment is principally unknown. Here, the immune landscape of ASCL1-positive lung adenocarcinomas was characterized by immunohistochemistry. Furthermore, ASCL1 was transduced in mouse lung adenocarcinoma cell lines and comparative RNA-sequencing and secretome analyses were performed. The effects of ASCL1 on tumorigenesis were explored in an orthotopic syngeneic transplantation model.ASCL1-positive lung adenocarcinomas revealed lower infiltration of CD8(+), CD4(+), CD20(+), and FOXP3(+) lymphocytes and CD163(+) macrophages indicating an immune desert phenotype. Ectopic ASCL1 upregulated cyclin transcript levels, stimulated cell proliferation, and enhanced tumor growth in mice. ASCL1 suppressed secretion of chemokines, including CCL20, CXCL2, CXCL10, and CXCL16, indicating effects on immune cell trafficking. In accordance with lower lymphocytes infiltration, ASCL1-positive lung adenocarcinomas demonstrated lower abundance of CXCR3-and CCR6-expressing cells.In conclusion, ASCL1 mediates its tumor-promoting effect not only through cell-autonomous signaling but also by modulating chemokine production and immune responses. These findings suggest that ASCL1-positive tumors represent a clinically relevant lung cancer entity.