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PD-L1 promotes myofibroblastic activation of hepatic stellate cells by distinct mechanisms selective for TGF-β receptor I versus II
- Source :
- Cell Reports, Vol 38, Iss 6, Pp 110349- (2022)
- Publication Year :
- 2022
- Publisher :
- Elsevier, 2022.
-
Abstract
- Summary: Intrahepatic cholangiocarcinoma (ICC) contains abundant myofibroblasts derived from hepatic stellate cells (HSCs) through an activation process mediated by TGF-β. To determine the role of programmed death-ligand 1 (PD-L1) in myofibroblastic activation of HSCs, we disrupted PD-L1 of HSCs by shRNA or anti-PD-L1 antibody. We find that PD-L1, produced by HSCs, is required for HSC activation by stabilizing TGF-β receptors I (TβRI) and II (TβRII). While the extracellular domain of PD-L1 (amino acids 19–238) targets TβRII protein to the plasma membrane and protects it from lysosomal degradation, a C-terminal 260-RLRKGR-265 motif on PD-L1 protects TβRI mRNA from degradation by the RNA exosome complex. PD-L1 is required for HSC expression of tumor-promoting factors, and targeting HSC PD-L1 by shRNA or Cre/loxP recombination suppresses HSC activation and ICC growth in mice. Thus, myofibroblast PD-L1 can modulate the tumor microenvironment and tumor growth by a mechanism independent of immune suppression.
Details
- Language :
- English
- ISSN :
- 22111247
- Volume :
- 38
- Issue :
- 6
- Database :
- Directory of Open Access Journals
- Journal :
- Cell Reports
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.9ce8462951c41878250cb90b74ca0e3
- Document Type :
- article
- Full Text :
- https://doi.org/10.1016/j.celrep.2022.110349