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Rho‐associated protein kinase‐dependent moesin phosphorylation is required for PD‐L1 stabilization in breast cancer

Expression of programmed cell death ligand (PD‐L1) is associated with poor prognosis in breast cancer. Understanding the regulation of PD‐L1 expression in breast cancer could provide a new strategy for breast cancer treatment. Here, we demonstrate that moesin (MSN) phosphorylation by Rho‐associated...

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Detalles Bibliográficos
Autores principales: Meng, Fanbiao, Su, Yang, Xu, Bo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607174/
https://www.ncbi.nlm.nih.gov/pubmed/32941674
http://dx.doi.org/10.1002/1878-0261.12804
Descripción
Sumario:Expression of programmed cell death ligand (PD‐L1) is associated with poor prognosis in breast cancer. Understanding the regulation of PD‐L1 expression in breast cancer could provide a new strategy for breast cancer treatment. Here, we demonstrate that moesin (MSN) phosphorylation by Rho‐associated protein kinase (ROCK) stabilizes PD‐L1 protein levels. Our results indicate that phosphorylated MSN may compete with the E3 ubiquitin ligase SPOP for binding PD‐L1. ROCK inhibition via the Y‐27632 inhibitor or MSN silencing decreased PD‐L1 expression, resulting in T‐cell activation both in vitro and in vivo. Administration of Y‐27632 into immunocompetent Balb/c mice bearing breast tumors suppressed tumor progression and enhanced CD4+ and CD8+ T‐cell infiltration. RNA‐seq analysis of Y‐27632‐treated mouse tumors revealed that ROCK inhibition upregulated several immune response genes. However, the combination of Y‐27632 and an anti‐PD‐1 antibody did not show additive or synergistic effects due to reduced PD‐L1 in the presence of Y‐27632. Our study unravels a previously unappreciated mechanism of PD‐L1 regulation through the ROCK‐MSN pathway. Moreover, we found that ROCK inhibitors could be combined with breast cancer immunotherapy.