Dataset Information

Transmural Flow Upregulates PD-L1 Expression in Microvascular Networks.

ABSTRACT: Endothelial programmed death-ligand 1 (PD-L1) expression is higher in tumors than in normal tissues. Also, tumoral vasculatures tend to be leakier than normal vessels leading to a higher trans-endothelial or transmural fluid flow. However, it is not clear whether such elevated transmural flow can control endothelial PD-L1 expression. Here, a new microfluidic device is developed to investigate the relationship between transmural flow and PD-L1 expression in microvascular networks (MVNs). After treating the MVNs with transmural flow for 24 h, the expression of PD-L1 in endothelial cells is upregulated. Additionally, CD8 T cell activation by phytohemagglutinin (PHA) is suppressed when cultured in the MVNs pre-conditioned with transmural flow. Moreover, transmural flow is able to further increase PD-L1 expression in the vessels formed in the tumor microenvironment. Finally, by utilizing blocking antibodies and knock-out assays, it is found that transmural flow-driven PD-L1 upregulation is controlled by integrin α_Vβ₃. Overall, this study provides a new biophysical explanation for high PD-L1 expression in tumoral vasculatures.

SUBMITTER: Wan Z

PROVIDER: S-EPMC11234398 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Transmural Flow Upregulates PD-L1 Expression in Microvascular Networks.

Wan Zhengpeng Z Zhang Shun S Zhong Amy X AX Xu Liling L Coughlin Mark F MF Pavlou Georgios G Shelton Sarah E SE Nguyen Huu Tuan HT Hirose Satomi S Kim Seunggyu S Floryan Marie A MA Barbie David A DA Hodi F Stephen FS Kamm Roger D RD

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20240502 26

Endothelial programmed death-ligand 1 (PD-L1) expression is higher in tumors than in normal tissues. Also, tumoral vasculatures tend to be leakier than normal vessels leading to a higher trans-endothelial or transmural fluid flow. However, it is not clear whether such elevated transmural flow can control endothelial PD-L1 expression. Here, a new microfluidic device is developed to investigate the relationship between transmural flow and PD-L1 expression in microvascular networks (MVNs). After tr ...[more]

PMID: 38696611

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Project description:BackgroundUpregulation of the PD-L1 (CD274) immune checkpoint ligand on the tumor surface facilitates tumor immune escape and limits the application of immunotherapy in various cancers, including breast cancer. However, the mechanisms underlying high PD-L1 levels in cancers are still poorly understood.MethodsBioinformatics analyses and in vivo and in vitro experiments were carried out to assess the association between CD8+ T lymphocytes and TIMELESS (TIM) expression, and to discover the mechanisms of TIM, the transcription factor c-Myc, and PD-L1 in breast cancer cell lines.ResultsThe circadian gene TIM enhanced PD-L1 transcription and facilitated the aggressiveness and progression of breast cancer through the intrinsic and extrinsic roles of PD-L1 overexpression. Bioinformatic analyses of our RNA sequencing data in TIM-knockdown breast cancer cells and public transcriptomic datasets showed that TIM might play an immunosuppressive role in breast cancer. We found that TIM expression was inversely associated with CD8+ T lymphocyte infiltration in human breast cancer samples and subcutaneous tumor tissues. In vivo and in vitro experiments demonstrated that TIM knockdown increased CD8+ T lymphocyte antitumor activity. Furthermore, our results showed that TIM interacts with c-Myc to enhance the transcriptional capability of PD-L1 and facilitates the aggressiveness and progression of breast cancer through the intrinsic and extrinsic roles of PD-L1 overexpression. Moreover, public database analysis suggested that high TIM levels were positively related to PD-L1 inhibitor therapeutic response.ConclusionsMechanistically, we first found that TIM could upregulate PD-L1 by interacting with c-Myc to enhance the transcriptional capability of c-Myc to PD-L1. Altogether, our findings not only provide a novel therapeutic strategy to treat breast cancer by targeting the oncogenic effect of TIM but also indicate that TIM is a promising biomarker for predicting the benefit of anti-PD-L1 immunotherapy.

Dataset Information

Transmural Flow Upregulates PD-L1 Expression in Microvascular Networks.

Publications

Transmural Flow Upregulates PD-L1 Expression in Microvascular Networks.

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