PD-L1 promotes myofibroblastic activation of hepatic stellate cells by distinct mechanisms selective for TGF-β receptor I versus II

Liankang Sun, Yuanguo Wang, Xianghu Wang, Amaia Navarro-Corcuera, Sumera Ilyas, Nidhi Jalan-Sakrikar, Can Gan, Xinyi Tu, Yu Shi, Kangsheng Tu, Qingguang Liu, Zhenkun Lou, Haidong Dong, Arlene H. Sharpe, Vijay H. Shah, Ningling Kang

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number110349
JournalCell reports
Volume38
Issue number6
DOIs
StatePublished - Feb 8 2022

Keywords

  • RNA immunoprecipitation
  • RNA sequencing
  • TGF-β receptor trafficking
  • biotinylation
  • cancer desmoplastic reaction
  • cancer-associated fibroblasts
  • conditional knockout mice
  • exosome component 10
  • ubiquitination
  • α-smooth muscle actin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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