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

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

  • Cell Rep. 2022 Feb 8;38(6):110349. doi: 10.1016/j.celrep.2022.110349.
Liankang Sun 1,  Yuanguo Wang 2,  Xianghu Wang 2,  Amaia Navarro-Corcuera 1,  Sumera Ilyas 1,  Nidhi Jalan-Sakrikar 1,  Can Gan 1,  Xinyi Tu 3,  Yu Shi 3,  Kangsheng Tu 4,  Qingguang Liu 4,  Zhenkun Lou 3,  Haidong Dong 5,  Arlene H Sharpe 6,  Vijay H Shah 7,  Ningling Kang 8
Affiliations

Affiliations

  • 1 GI Research Unit and Cancer Cell Biology Program, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1(st) ST SW, Rochester, MN 55905, USA.
  • 2 Tumor Microenvironment and Metastasis, the Hormel Institute, University of Minnesota, 801 16(th) Ave NE, Austin, MN 55912, USA.
  • 3 Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
  • 4 Department of Hepatobiliary Surgery, 1st Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China.
  • 5 Department of Urology, Mayo Clinic, Rochester, MN 55905, USA; Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.
  • 6 Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
  • 7 GI Research Unit and Cancer Cell Biology Program, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1(st) ST SW, Rochester, MN 55905, USA. Electronic address: shah.vijay@mayo.edu.
  • 8 Tumor Microenvironment and Metastasis, the Hormel Institute, University of Minnesota, 801 16(th) Ave NE, Austin, MN 55912, USA. Electronic address: nkang@umn.edu.
PMID: 35139382 DOI: 10.1016/j.celrep.2022.110349
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.

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.

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