Department of Obstetrics and Gynecology, Changzhou Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Changzhou 213003, Jiangsu Province, China.
Changzhou Maternity and Child Health Care Hospital affiliated to Nanjing Medical University.
Crit Rev Eukaryot Gene Expr. 2024;34(8):35-45. doi: 10.1615/CritRevEukaryotGeneExpr.2024053577.
Foxm1 functions as an oncogene in multiple human malignancies, including cervical cancer. However, the potential of Foxm1 in the tumor microenvironment (TME) is still unknown. The purpose of the present study is to investigate the role of Foxm1 in CD8+ T cell anti-tumor immunity. RT-qPCR is conducted to calculate mRNA levels. JASPAR is used to predict the binding sites between Foxm1 and NLRP3. ChIP assay is performed to verify the occupancy of Foxm1 on the promoter of NLRP3. Modulatory relationship between Foxm1 and NLRP3 is verified by luciferase assay. In vivo assays are conducted to further verify the role of Foxm1/NLRP3 axis in cervical cancer. HE staining assay is applied for histological analysis. Flow cytometry is conducted to determine the functions of immune cells. We found that Foxm1 knockdown decreases tumor burden and suppresses tumor growth of cervical cancer. Foxm1 knock-down promotes the infiltration of CD8+ T cells. Foxm1 deficiency inhibits the exhaustion of CD8+ T cells and facilitates the maintenance of CD8+ effector and stem-like T cells. Moreover, Foxm1 transcriptionally inactivates NLRP3 and suppresses the expression of innate cytokines IL-1β and IL-18. However, inhibition of NLRP3 inflammasome or neutralizing IL-1β and IL-18 inhibits anti-tumor immunity and promoted tumor growth in Foxm1 deficiency in CD8+ T cells. In summary, targeting Foxm1 mediates the activation of NLRP3 inflammasome and stimulates CD8+ T cell anti-tumor immunity in cervical cancer.
Foxm1 在多种人类恶性肿瘤中发挥癌基因作用，包括宫颈癌。然而，Foxm1 在肿瘤微环境（TME）中的潜力尚不清楚。本研究旨在研究 Foxm1 在 CD8+T 细胞抗肿瘤免疫中的作用。通过 RT-qPCR 计算 mRNA 水平。JASPAR 用于预测 Foxm1 与 NLRP3 之间的结合位点。ChIP 测定用于验证 Foxm1 在 NLRP3 启动子上的占据。通过荧光素酶测定验证 Foxm1 和 NLRP3 之间的调节关系。进行体内测定进一步验证 Foxm1/NLRP3 轴在宫颈癌中的作用。进行 HE 染色测定进行组织学分析。进行流式细胞术确定免疫细胞的功能。我们发现 Foxm1 敲低可减少肿瘤负担并抑制宫颈癌的生长。Foxm1 敲低可促进 CD8+T 细胞的浸润。Foxm1 缺乏抑制 CD8+T 细胞的耗竭并促进 CD8+效应和干细胞样 T 细胞的维持。此外，Foxm1 转录失活 NLRP3 并抑制先天细胞因子 IL-1β和 IL-18 的表达。然而，抑制 NLRP3 炎性小体或中和 IL-1β 和 IL-18 可抑制 Foxm1 缺乏的 CD8+T 细胞中的抗肿瘤免疫并促进肿瘤生长。总之，靶向 Foxm1 介导 NLRP3 炎性小体的激活，并刺激宫颈癌中 CD8+T 细胞的抗肿瘤免疫。
