Department of General Surgery, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, P.R. China.
Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, P.R. China.
Immun Inflamm Dis. 2022 Nov;10(11):e727. doi: 10.1002/iid3.727.
Hilar cholangiocarcinoma (HCCA) is a malignancy related to chronic biliary tract inflammation. Tumor immune escape is a necessary process of tumorigenesis. Forkhead box M1 (FoxM1) could affect the progression of various carcinomas. This study attempted to elaborate on the mechanism of FoxM1 in HCCA immune escape.
HCCA cell lines were collected to measure the expression of FoxM1 and FoxP3. CD8 T cells were extracted to establish the co-culture system with HCCA cells and Treg cells. pcDNA3.1-FoxM1 or si-FoxP3 was transfected into HCCA cells in the co-culture system. HCCA cell viability, mobility, and invasiveness as well as levels of transforming growth factor (TGF)-β and interleukin (IL)-6 were evaluated. The binding relation between FoxM1 and FoxP3 promoter was verified. HCCA cells with pcDNA3.1-FoxM1 were subcutaneously injected into mice to establish the xenograft mouse models.
FoxM1 and FoxP3 were overexpressed in HCCA cells. The co-culture of CD8 T and HCCA cells inhibited HCCA cell activity and Treg cells limited CD8 T killing. FoxM1 overexpression strengthened the inhibiting role of Treg cells in CD8 T killing, upregulated TGF-β and IL-6 levels, and encouraged HCCA immune escape. FoxM1 bound to the FoxP3 promoter region to promote FoxP3 transcription. Silencing of FoxP3 neutralized the promoting role of FoxM1 overexpression in Treg cell immunosuppression and HCCA cell immune escape. FoxM1 aggravated tumor development, upregulated FoxP3 expression, increased Treg cells, and reduced CD8 T cells.
FoxM1 bound to the FoxP3 promoter region to promote FoxP3 transcription and recruited FoxP3 Treg cells, thereby inducing HCCA immune escape.
肝门部胆管癌（HCCA）是一种与慢性胆道炎症相关的恶性肿瘤。肿瘤免疫逃逸是肿瘤发生的必要过程。叉头框 M1（FoxM1）可影响多种癌的进展。本研究试图阐述 FoxM1 在 HCCA 免疫逃逸中的机制。
收集 HCCA 细胞系，测量 FoxM1 和 FoxP3 的表达。提取 CD8 T 细胞，与 HCCA 细胞和 Treg 细胞建立共培养系统。将 pcDNA3.1-FoxM1 或 si-FoxP3 转染到共培养系统中的 HCCA 细胞中。评估 HCCA 细胞活力、迁移和侵袭能力以及转化生长因子-β（TGF-β）和白细胞介素（IL）-6 水平。验证 FoxM1 与 FoxP3 启动子之间的结合关系。将 pcDNA3.1-FoxM1 的 HCCA 细胞皮下注射到小鼠中，建立异种移植小鼠模型。
FoxM1 和 FoxP3 在 HCCA 细胞中过表达。CD8 T 和 HCCA 细胞的共培养抑制 HCCA 细胞活性，Treg 细胞限制 CD8 T 杀伤。FoxM1 过表达增强了 Treg 细胞对 CD8 T 杀伤的抑制作用，上调了 TGF-β和 IL-6 水平，并促进了 HCCA 免疫逃逸。FoxM1 结合到 FoxP3 启动子区域，促进 FoxP3 转录。沉默 FoxP3 中和了 FoxM1 过表达对 Treg 细胞免疫抑制和 HCCA 细胞免疫逃逸的促进作用。FoxM1 加重肿瘤发展，上调 FoxP3 表达，增加 Treg 细胞，减少 CD8 T 细胞。
FoxM1 结合到 FoxP3 启动子区域，促进 FoxP3 转录，并募集 FoxP3 Treg 细胞，从而诱导 HCCA 免疫逃逸。
