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

doi:10.1016/j.celrep.2022.110349

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

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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)
Article number	110349
Journal	Cell reports
Volume	38
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2022.110349
State	Published - Feb 8 2022

Bibliographical note

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2022.110349

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Sun, L., Wang, Y., Wang, X., Navarro-Corcuera, A., Ilyas, S., Jalan-Sakrikar, N., Gan, C., Tu, X., Shi, Y., Tu, K., Liu, Q., Lou, Z., Dong, H., Sharpe, A. H., Shah, V. H., & Kang, N. (2022). PD-L1 promotes myofibroblastic activation of hepatic stellate cells by distinct mechanisms selective for TGF-β receptor I versus II. Cell reports, 38(6), Article 110349. https://doi.org/10.1016/j.celrep.2022.110349

Sun, L, Wang, Y, Wang, X, Navarro-Corcuera, A, Ilyas, S, Jalan-Sakrikar, N, Gan, C, Tu, X, Shi, Y, Tu, K, Liu, Q, Lou, Z, Dong, H, Sharpe, AH, Shah, VH & Kang, N 2022, 'PD-L1 promotes myofibroblastic activation of hepatic stellate cells by distinct mechanisms selective for TGF-β receptor I versus II', Cell reports, vol. 38, no. 6, 110349. https://doi.org/10.1016/j.celrep.2022.110349

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

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.",

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AU - Sun, Liankang

AU - Wang, Yuanguo

AU - Wang, Xianghu

AU - Navarro-Corcuera, Amaia

AU - Ilyas, Sumera

AU - Jalan-Sakrikar, Nidhi

AU - Gan, Can

AU - Tu, Xinyi

AU - Shi, Yu

AU - Tu, Kangsheng

AU - Liu, Qingguang

AU - Lou, Zhenkun

AU - Dong, Haidong

AU - Sharpe, Arlene H.

AU - Shah, Vijay H.

AU - Kang, Ningling

PY - 2022/2/8

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N2 - 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.

AB - 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.

KW - RNA immunoprecipitation

KW - RNA sequencing

KW - TGF-β receptor trafficking

KW - biotinylation

KW - cancer desmoplastic reaction

KW - cancer-associated fibroblasts

KW - conditional knockout mice

KW - exosome component 10

KW - ubiquitination

KW - α-smooth muscle actin

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VL - 38

JO - Cell reports

JF - Cell reports

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ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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