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

The Hormel Institute

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

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

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

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), [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.",

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",

author = "Liankang Sun and Yuanguo Wang and Xianghu Wang and Amaia Navarro-Corcuera and Sumera Ilyas and Nidhi Jalan-Sakrikar and Can Gan and Xinyi Tu and Yu Shi and Kangsheng Tu and Qingguang Liu and Zhenkun Lou and Haidong Dong and Sharpe, {Arlene H.} and Shah, {Vijay H.} and Ningling Kang",

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: {\textcopyright} 2022 The Authors",

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doi = "10.1016/j.celrep.2022.110349",

language = "English (US)",

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T1 - PD-L1 promotes myofibroblastic activation of hepatic stellate cells by distinct mechanisms selective for TGF-β receptor I versus II

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

N1 - 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

PY - 2022/2/8

Y1 - 2022/2/8

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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DO - 10.1016/j.celrep.2022.110349

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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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