期刊
MOLECULAR ONCOLOGY
卷 14, 期 11, 页码 2701-2712出版社
WILEY
DOI: 10.1002/1878-0261.12804
关键词
MSN; PD-L1; ROCK inhibitor; T-cell immune response
类别
资金
- National Natural Science Foundation of China [81672743, 81974464]
- National Key Projects of Research and Development of China [2016YFC0904601]
- Tianjin Natural Science Foundation for Youths [18JCQNJC79800]
- Shenzhen Basic Research Project [JCYJ20160331114230843]
- Shenzhen Science and Technology Innovation Commission [GJHS20170313110507326]
- Youth Foundation of Tianjin Medical University Cancer Institute and Hospital [B1714]
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 bothin vitroandin 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.
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