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

Dawei Rong1, Yuliang Wang2, Li Liu3

  • 1Hepatobiliary 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.

Journal for Immunotherapy of Cancer
|February 14, 2023
PubMed
Abstract

Insights

GLI-similar 1 (GLIS1) promotes CD8+ T cell exhaustion in liver cancer (HCC). Downregulating GLIS1 enhances T cell anti-cancer activity and synergizes with anti-PD1 therapy for potential HCC immune treatment.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • GLI-similar 1 (GLIS1) is a Krüppel-like zinc finger protein involved in gene transcription.
  • The specific role of GLIS1 in T cell function, particularly in cancer, remained largely unexplored.

Purpose of the Study:

  • To investigate the impact of GLIS1 on the anti-cancer efficacy of CD8+ T cells in hepatocellular carcinoma (HCC).
  • To elucidate the molecular mechanisms by which GLIS1 influences T cell exhaustion and anti-tumor immunity in HCC.

Main Methods:

  • Quantification of GLIS1 expression in CD8+ T cells from HCC patients and mouse models.
  • Assessment of CD8+ T cell anti-cancer potency following GLIS1 knockdown in vitro and in vivo.
  • Analysis of the tumor immune microenvironment in GLIS1 knockout mice.
  • Chromatin immunoprecipitation and RNA sequencing to identify GLIS1-regulated pathways.

Main Results:

  • GLIS1 expression is elevated in exhausted CD8+ T cells within HCC.
  • GLIS1 downregulation enhances CD8+ T cell infiltration, reduces exhaustion, and improves anti-PD1 therapy response in HCC models.
  • GLIS1 directly regulates the SGK1-STAT3-PD1 pathway, maintaining PD1 expression on CD8+ T cells.

Conclusions:

  • GLIS1 promotes CD8+ T cell exhaustion in HCC via the SGK1-STAT3-PD1 pathway.
  • Targeting GLIS1 in CD8+ T cells offers a promising synergistic strategy with anti-PD1 immunotherapy for HCC treatment.
Keywords:
biomarkers, tumordrug therapy, combinationimmunity, cellular

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