Transmural Flow Upregulates PD‐L1 Expression in Microvascular Networks

Author:

Wan Zhengpeng12,Zhang Shun134,Zhong Amy X.1,Xu Liling5,Coughlin Mark F.1,Pavlou Georgios1,Shelton Sarah E.12,Nguyen Huu Tuan1,Hirose Satomi1,Kim Seunggyu1,Floryan Marie A.1,Barbie David A.2,Hodi F. Stephen26,Kamm Roger D.17ORCID

Affiliation:

1. Department of Biological Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA

2. Department of Medical Oncology Dana‐Farber Cancer Institute Boston MA 02215 USA

3. State Key Laboratory of Organ Regeneration and Reconstruction Institute of Zoology Chinese Academy of Sciences Beijing 100101 China

4. Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101 China

5. Ragon Institute of MGH MIT and Harvard Cambridge MA 02139 USA

6. Parker Institute for Cancer Immunotherapy Boston MA 02215 USA

7. Department of Mechanical Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA

Abstract

AbstractEndothelial 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 αVβ3. Overall, this study provides a new biophysical explanation for high PD‐L1 expression in tumoral vasculatures.

Funder

National Cancer Institute

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

Publisher

Wiley

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