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
  • 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: [email protected].
  • 8. Tumor Microenvironment and Metastasis, the Hormel Institute, University of Minnesota, 801 16(th) Ave NE, Austin, MN 55912, USA. Electronic address: [email protected].
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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