2. Academic Validation
  3. GLIS1 intervention enhances anti-PD1 therapy for hepatocellular carcinoma by targeting SGK1-STAT3-PD1 pathway

GLIS1 intervention enhances anti-PD1 therapy for hepatocellular carcinoma by targeting SGK1-STAT3-PD1 pathway

  • J Immunother Cancer. 2023 Feb;11(2):e005126. doi: 10.1136/jitc-2022-005126.
Dawei Rong # 1,  Yuliang Wang # 2,  Li Liu # 3,  Hengsong Cao # 1,  Tian Huang 1,  Hanyuan Liu 1,  Xiaopei Hao 1,  Guangshun Sun 1,  Guoqiang Sun 1,  Zhiying Zheng 1,  Junwei Kang 1,  Yongxiang Xia 4,  Ziyi Chen 4,  Weiwei Tang 4,  Xuehao Wang 4
Affiliations

Affiliations

  • 1 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China.
  • 2 School of Basic Medicine, Nanjing Medical University, Nanjing, China.
  • 3 Tianjin University of Traditional Chinese Medicine, Tianjin, China.
  • 4 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China wangxh@njmu.edu.cn 1243773473twww@sina.com dr_czy@126.com yx_xia@njmu.edu.cn.
  • # Contributed equally.
PMID: 36787938 DOI: 10.1136/jitc-2022-005126
Abstract

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.

Keywords

biomarkers, tumor; drug therapy, combination; immunity, cellular.

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