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
Affiliations
Liankang Sun
GI Research Unit and Cancer Cell Biology Program, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st ST SW, Rochester, MN 55905, USA
Yuanguo Wang
Tumor Microenvironment and Metastasis, the Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, USA
Xianghu Wang
Tumor Microenvironment and Metastasis, the Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, USA
Amaia Navarro-Corcuera
GI Research Unit and Cancer Cell Biology Program, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st ST SW, Rochester, MN 55905, USA
Sumera Ilyas
GI Research Unit and Cancer Cell Biology Program, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st ST SW, Rochester, MN 55905, USA
Nidhi Jalan-Sakrikar
GI Research Unit and Cancer Cell Biology Program, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st ST SW, Rochester, MN 55905, USA
Can Gan
GI Research Unit and Cancer Cell Biology Program, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st ST SW, Rochester, MN 55905, USA
Xinyi Tu
Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
Yu Shi
Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
Kangsheng Tu
Department of Hepatobiliary Surgery, 1st Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China
Qingguang Liu
Department of Hepatobiliary Surgery, 1st Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China
Zhenkun Lou
Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
Haidong Dong
Department of Urology, Mayo Clinic, Rochester, MN 55905, USA; Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA
Arlene H. Sharpe
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA
Vijay H. Shah
GI Research Unit and Cancer Cell Biology Program, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st ST SW, Rochester, MN 55905, USA; Corresponding author
Ningling Kang
Tumor Microenvironment and Metastasis, the Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, USA; Corresponding author
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.
