Foxm1-Mediated Transcriptional Inactivation of NLRP3 Inflammasome Promotes Immunosuppression in Cervical Cancer.

ABSTRACT

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-1ß and IL-18. However, inhibition of NLRP3 inflammasome or neutralizing IL-1ß 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.