Dataset Information

Role of Forkhead Box P3 in IFNγ-Mediated PD-L1 Expression and Bladder Cancer Epithelial-to-Mesenchymal Transition.

ABSTRACT: Antagonism of the PD-1/PD-L1 axis is a critical therapeutic strategy for patients with advanced bladder cancer. IFNγ functions as a key regulator of PD-L1 in both immune as well as cancer cells. Forkhead box P3 (FOXP3) is a transcription factor synonymous in T regulatory cell function but with increasingly described functions in cancer cells. Here, we investigated the relationship between FOXP3 and PD-L1 in bladder cancer. We showed that FOXP3 is critical in the ability for IFNγ to activate PD-L1 in bladder cancer cells. FOXP3 can bind to the PD-L1 promoter and induces a gene program that leads to regulation of multiple immune-related genes and genes involved in epithelial-to-mesenchymal transition (EMT). Using in vitro and in vivo human and murine models, we showed that FOXP3 can influence bladder cancer EMT as well as promote cancer metastases. Furthermore, FOXP3 may be a convergent factor for multiple activators of PD-L1, including the chemotherapeutic drug cisplatin.

Significance

Historically a key transcription factor driving T regulatory cell function, FOXP3 has an increasingly recognized role in cancer cells. In bladder cancer, we defined a novel mechanism whereby FOXP3 mediates the activation of the immune checkpoint PD-L1 by the cytokine IFNγ. We also showed that FOXP3 induces other immune checkpoints as well as genes involved in EMT, promoting immune resistance and cancer metastases.

SUBMITTER: Zhang H

PROVIDER: S-EPMC11345674 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Publications

Role of Forkhead Box P3 in IFNγ-Mediated PD-L1 Expression and Bladder Cancer Epithelial-to-Mesenchymal Transition.

Zhang Hanwei H Ly Ann A Chou Emily E Wang Liang L Zhang Paul P Prado Kris K Gu Yiqian Y Pellegrini Matteo M Chin Arnold I AI

Cancer research communications 20240801 8

Antagonism of the PD-1/PD-L1 axis is a critical therapeutic strategy for patients with advanced bladder cancer. IFNγ functions as a key regulator of PD-L1 in both immune as well as cancer cells. Forkhead box P3 (FOXP3) is a transcription factor synonymous in T regulatory cell function but with increasingly described functions in cancer cells. Here, we investigated the relationship between FOXP3 and PD-L1 in bladder cancer. We showed that FOXP3 is critical in the ability for IFNγ to activate PD-L ...[more]

PMID: 39099201

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Project description:BackgroundEpithelial-mesenchymal transition (EMT) is regarded as a key process in repair of airway epithelium after injury. Forkhead Box C2 (FOXC2) is a transcription factor involved in EMT process, whether it is involved in repair of bronchial epithelium remains unknown.MethodsC57BL/6 mice were subjected to intraperitoneal injection with naphthalene (NAPH; 200 mg/kg) to induce airway injury model. qPCR, immunoblot and FOXC2 immunohistochemistry assays were conducted to detect the expression of FOXC2 in bronchial epithelium. To explore the function of FOXC2 in NAPH-induced airway injury, the mice were given intratracheal administration of shFOXC2- or shNC-lentivirus particles, followed by NAPH treatment. Hematoxylin-and-eosin staining was used to assess the histopathology of the bronchial epithelium. Immunofluorescence analysis of CCSP, a club cell marker confirmed the CCSP expression in bronchial epithelium. Immunoblot and immunofluorescence assays determined the expression of E-cadherin, vimentin, and N-cadherin. In mouse primary bronchial epithelial cells (PBECs), we overexpressed and silenced FOXC2 by lentivirus particles, respectively. Cell migration was analyzed using wound healing assay. Immunoblot assays determined the E-cadherin, vimentin, FN-EDA expression in TGF-β1-induced PBECs. mRNA sequencing (mRNA-seq) and FOXC2 ChIP sequencing (ChIP-seq) to reveal the downstream genes of FOXC2 in TGF-β1-induced PBECs. Luciferase assay, ChIP-PCR and functional rescue experiments were performed to confirm the interaction of FOXC2/formin binding protein 1 (FNBP1) in TGF-β1-induced PBECs.ResultsFOXC2 expression was up-regulated in the lung tissues of mice at 2, 3 and 6 days post-NAPH. FOXC2 knockdown in bronchial epithelium of mice delayed CCSP+ club cell regeneration and normal repair of the airway epithelium within 14 days after injury. Knockdown of FOXC2 increased E-cadherin but decreased vimentin and N-cadherin, EMT markers during early phase after injury. In vitro, knockdown of endogenous FOXC2 repressed the migration of cells and increased TGF-β1-induced E-cadherin but decreased vimentin, N-cadherin and FN-EDA. Exogenous FOXC2 addition exerted opposite effects. Furthermore, mRNA-seq and FOXC2 ChIP-seq revealed that FNBP1 might be a downstream target of FOXC2. Overexpression of FNBP1 reversed the inhibitory role of FOXC2 knockdown in EMT.ConclusionsThese data highlight the important function of FOXC2 as a regulator in repair of bronchial epithelium after injury.

Dataset Information

Role of Forkhead Box P3 in IFNγ-Mediated PD-L1 Expression and Bladder Cancer Epithelial-to-Mesenchymal Transition.

Significance

Publications

Role of Forkhead Box P3 in IFNγ-Mediated PD-L1 Expression and Bladder Cancer Epithelial-to-Mesenchymal Transition.

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