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 language | English (US) |
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Article number | 110349 |
Journal | Cell reports |
Volume | 38 |
Issue number | 6 |
DOIs | |
State | Published - Feb 8 2022 |
Bibliographical note
Funding Information:NIH grants R01CA160069 R01CA187027 to N.K., R37AA021171 to V.H.S., the Cell Biology Core of the Mayo Clinic Center for Cell Signaling in Gastroenterology ( P30DK084567 ), and the Mayo Clinic Hepatobiliary SPORE ( P50 CA210964 ) Developmental Research Program. L.S. is funded by the China Scholarship Council .
Funding Information:
NIH grants R01CA160069 R01CA187027 to N.K. R37AA021171 to V.H.S. the Cell Biology Core of the Mayo Clinic Center for Cell Signaling in Gastroenterology (P30DK084567), and the Mayo Clinic Hepatobiliary SPORE (P50 CA210964) Developmental Research Program. L.S. is funded by the China Scholarship Council. L.S. Y.W. X.W. S.I. N.J.-S. and C.G. performed in vitro experiments and tumor implantation studies in mice. A.N.-C. analyzed RNA sequencing data using a bioinformatics approach. X.T. Z.L. Y.S. H.D. K.T. Q.L. and A.H.S. generated experiment reagents for this study. N.K. and V.H.S. provided the direction for this project, analyzed the data, and wrote this manuscript together with L.S. The authors declare no competing interests. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. We worked to ensure that the study questionnaires were prepared in an inclusive way. We worked to ensure diversity in experimental samples through the selection of the cell lines.
Publisher Copyright:
© 2022 The Authors
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