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GLIS1 intervention enhances anti-PD1 therapy for hepatocellular carcinoma by targeting SGK1-STAT3-PD1 pathway
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 pote...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9930610/ https://www.ncbi.nlm.nih.gov/pubmed/36787938 http://dx.doi.org/10.1136/jitc-2022-005126 |
Sumario: | 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. |
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