FOXM1 Inhibition Enhances the Therapeutic Outcome of Lung Cancer Immunotherapy by Modulating PD‐L1 Expression and Cell Proliferation

Abstract

Programmed death-ligand 1 (PD-L1) is a major target to cancer immunotherapy, and anti-PD-L1 and anti-PD-1 antibody-mediated immunotherapy are being increasingly used. However, immune checkpoint inhibitors (ICIs) are ineffective in treating large tumors and cause various immune-related adverse events in nontarget organs, including life-threatening cardiotoxicity. Therefore, the development of new therapeutic strategies to overcome these limitations is crucial. The focus of this study is the forkhead box protein M1 (FOXM1), which is identified as a potential therapeutic target for cancer immunotherapy and is associated with the modulation of PD-L1 expression. Selective small interfering RNA knockdown of FOXM1 or treatment with thiostrepton (TST) significantly reduces PD-L1 expression in non-small-cell lung cancer (NSCLC) cells and inhibits proliferation. Chromatin immunoprecipitation-PCR reveals that FOXM1 selectively upregulates PD-L1 expression by binding directly to the PD-L1 promoter. In vivo animal studies have shown that TST treatment significantly downregulates PD-L1 expression in human NSCLC tumors, while greatly reducing tumor size without side effects on normal tissues. Combined treatment with TST and anti-4-1BB antibody in the LLC-1 syngeneic tumor model induces synergistic therapeutic outcomes against immune resistant lung tumors as well as 2.72-folds higher CD3 + T cells in tumor tissues compared to that in the anti-4-1BB antibody treatment group.

Epigenomic Analyses Identify FOXM1 As a Key Regulator of Anti-Tumor Immune Response in Esophageal Adenocarcinoma

“…Using syngeneic murine models, we found that loss of FOXM1 resulted in heightened infiltration of CD8 + T cells into the tumor microenvironment, which was corroborated by in vitro CD8 + T cell chemotaxis assays. Interestingly, a recent study showed that upon inhibition of FOXM1 using Thiostrepton in Lewis lung carcinoma cells caused an increase in the number of intratumoral CD3 + T cells (41), in line with our observations. Ex vivo co-culture assays revealed that FOXM1 inhibited CD8 + T cell-mediated antigendependent killing of cancer cells.…”

Comprehensive analysis of FOXM1 immune infiltrates, m6a, glycolysis and ceRNA network in human hepatocellular carcinoma

“…Nonetheless, Increasing evidence for the increase of Tfh cells was associated with poor prognosis ( 45 , 46 ), and the rate of Tfh cell infiltration is higher in late-stage patients than in early-stage patients. Tfh cells also have known roles in the origin of T cell malignancies and assist malignant B cells ( 47 ). Besides, Tfh cells exacerbate immune-related adverse events, such as immune checkpoint blockade (ICB) and autoimmunity during cancer immunotherapy ( 48 ).…”

“…FOXM1 has also been found to recruit macrophage migration in FOXM1 in lung cancer (42). If only the biological functions of FOXM1 in the cell cycle and cell proliferation are malignancies and assist malignant B cells (47). Besides, Tfh cells exacerbate immune-related adverse events, such as immune checkpoint blockade (ICB) and autoimmunity during cancer immunotherapy (48).…”

Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets

“…[310][311][312] Histone modification: Forkhead box transcription factor M1 (FOXM1) has been reported to participate in oncogenesis by transcriptionally regulating of target genes in several cells, including DCs. [313][314][315] Recent studies have shown that FOXM1 delays the maturation of bone marrow-derived dendritic cells (BMDCs) and inhibits T-cell proliferation in tumor-bearing mice. Mechanistically, the enrichment of H3K79me2 in the FOXM1 promoter was observed, and FOXM1 expression was regulated by epigenetic inheritance.…”