| First Author | Sun L | Year | 2022 |
| Journal | Cell Rep | Volume | 38 |
| Issue | 6 | Pages | 110349 |
| PubMed ID | 35139382 | Mgi Jnum | J:320436 |
| Mgi Id | MGI:6874533 | Doi | 10.1016/j.celrep.2022.110349 |
| Citation | Sun L, et al. (2022) PD-L1 promotes myofibroblastic activation of hepatic stellate cells by distinct mechanisms selective for TGF-beta receptor I versus II. Cell Rep 38(6):110349 |
| abstractText | Intrahepatic cholangiocarcinoma (ICC) contains abundant myofibroblasts derived from hepatic stellate cells (HSCs) through an activation process mediated by TGF-beta. 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-beta receptors I (TbetaRI) and II (TbetaRII). While the extracellular domain of PD-L1 (amino acids 19-238) targets TbetaRII protein to the plasma membrane and protects it from lysosomal degradation, a C-terminal 260-RLRKGR-265 motif on PD-L1 protects TbetaRI 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. |
