GLIS1 intervention enhances anti-PD1 therapy for hepatocellular carcinoma by targeting SGK1-STAT3-PD1 pathway
© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ..
BACKGROUND: GLI-similar 1 (GLIS1) is one of of Krüppel-like zinc finger proteins, which are either stimulators or inhibitors of genetic transcription. Nevertheless, its effects on T cell were elusive.
METHODS: In this study, we intend to explore the effects of GLIS1 on modulating the anticancer potency of CD8+ T cells in hepatocellular carcinoma (HCC). The expression of GLIS1 in CD8 peripheral blood mononuclear cell and CD8 tumor-infiltrating lymphocytes of HCC tissues was validated by quantificational real-time-PCR and flow cytometry. The anticancer potency of CD8+ T cells with GLIS1 knock down was confirmed in C57BL/6 mouse model and HCC patient-derived xenograft mice model. GLIS1-/- C57BL/6 mice was applied to explore the effects GLIS1 on tumor immune microenvironment. Chromatin immunoprecipitation and RNA transcriptome sequencing analysis were both performed in GLIS1-knock down of CD8+ T cells.
RESULTS: GLIS1 was upregulated in exhausted CD8+ T cells in HCC. GLIS1 downregulation in CD8+ T cells repressed cancer development, elevated the infiltrate ability of CD8+ T cells, mitigated CD8+ T cell exhaustion and ameliorated the anti-PD1 reaction of CD8+ T cells in HCC. The causal link beneath this included transcriptional regulation of SGK1-STAT3-PD1 pathway by GLIS1, thereby maintaining the abundant PD1 expression on the surface of CD8+ T cells.
CONCLUSION: Our study revealed that GLIS1 promoted CD8+ T cell exhaustion in HCC through transcriptional regulating SGK1-STAT3-PD1 pathway. Downregulating the expression of GLIS1 in CD8+ T cells exerted an effect with anti-PD1 treatment synergistically, revealing a prospective method for HCC immune therapy.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2023 |
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Erschienen: |
2023 |
Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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Enthalten in: |
Journal for immunotherapy of cancer - 11(2023), 2 vom: 12. Feb. |
Sprache: |
Englisch |
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Beteiligte Personen: |
Rong, Dawei [VerfasserIn] |
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Links: |
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Anmerkungen: |
Date Completed 16.02.2023 Date Revised 24.02.2023 published: Print Citation Status MEDLINE |
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doi: |
10.1136/jitc-2022-005126 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM352945273 |
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245 | 1 | 0 | |a GLIS1 intervention enhances anti-PD1 therapy for hepatocellular carcinoma by targeting SGK1-STAT3-PD1 pathway |
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500 | |a Citation Status MEDLINE | ||
520 | |a © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. | ||
520 | |a BACKGROUND: GLI-similar 1 (GLIS1) is one of of Krüppel-like zinc finger proteins, which are either stimulators or inhibitors of genetic transcription. Nevertheless, its effects on T cell were elusive | ||
520 | |a METHODS: In this study, we intend to explore the effects of GLIS1 on modulating the anticancer potency of CD8+ T cells in hepatocellular carcinoma (HCC). The expression of GLIS1 in CD8 peripheral blood mononuclear cell and CD8 tumor-infiltrating lymphocytes of HCC tissues was validated by quantificational real-time-PCR and flow cytometry. The anticancer potency of CD8+ T cells with GLIS1 knock down was confirmed in C57BL/6 mouse model and HCC patient-derived xenograft mice model. GLIS1-/- C57BL/6 mice was applied to explore the effects GLIS1 on tumor immune microenvironment. Chromatin immunoprecipitation and RNA transcriptome sequencing analysis were both performed in GLIS1-knock down of CD8+ T cells | ||
520 | |a RESULTS: GLIS1 was upregulated in exhausted CD8+ T cells in HCC. GLIS1 downregulation in CD8+ T cells repressed cancer development, elevated the infiltrate ability of CD8+ T cells, mitigated CD8+ T cell exhaustion and ameliorated the anti-PD1 reaction of CD8+ T cells in HCC. The causal link beneath this included transcriptional regulation of SGK1-STAT3-PD1 pathway by GLIS1, thereby maintaining the abundant PD1 expression on the surface of CD8+ T cells | ||
520 | |a CONCLUSION: Our study revealed that GLIS1 promoted CD8+ T cell exhaustion in HCC through transcriptional regulating SGK1-STAT3-PD1 pathway. Downregulating the expression of GLIS1 in CD8+ T cells exerted an effect with anti-PD1 treatment synergistically, revealing a prospective method for HCC immune therapy | ||
650 | 4 | |a Journal Article | |
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700 | 1 | |a Wang, Yuliang |e verfasserin |4 aut | |
700 | 1 | |a Liu, Li |e verfasserin |4 aut | |
700 | 1 | |a Cao, Hengsong |e verfasserin |4 aut | |
700 | 1 | |a Huang, Tian |e verfasserin |4 aut | |
700 | 1 | |a Liu, Hanyuan |e verfasserin |4 aut | |
700 | 1 | |a Hao, Xiaopei |e verfasserin |4 aut | |
700 | 1 | |a Sun, Guangshun |e verfasserin |4 aut | |
700 | 1 | |a Sun, Guoqiang |e verfasserin |4 aut | |
700 | 1 | |a Zheng, Zhiying |e verfasserin |4 aut | |
700 | 1 | |a Kang, Junwei |e verfasserin |4 aut | |
700 | 1 | |a Xia, Yongxiang |e verfasserin |4 aut | |
700 | 1 | |a Chen, Ziyi |e verfasserin |4 aut | |
700 | 1 | |a Tang, Weiwei |e verfasserin |4 aut | |
700 | 1 | |a Wang, Xuehao |e verfasserin |4 aut | |
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