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A "Patient-Like" Orthotopic Syngeneic Mouse Model of Hepatocellular Carcinoma Metastasis
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GITR ligation enhances functionality of tumor-infiltrating T cells in hepatocellular carcinoma

Adriaan A van Beek1, Guoying Zhou1, Michail Doukas2

  • 1Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.

International Journal of Cancer
|February 6, 2019
PubMed

Insights

Agonistic targeting of GITR (glucocorticoid-induced tumor necrosis factor receptor) can enhance anti-tumor immunity in advanced hepatocellular carcinoma (HCC). This approach may offer new immunotherapy options for HCC patients when used alone or with PD-1 blockade.

Area of Science:

  • Immunology
  • Oncology
  • Cancer Research

Background:

  • Advanced hepatocellular carcinoma (HCC) lacks curative treatments.
  • Anti-PD1 antibody therapy shows potential but only benefits 20% of patients.
  • The role of co-stimulatory receptor agonists in HCC immunity is unknown.

Purpose of the Study:

  • To investigate if agonistic GITR targeting can enhance anti-tumor immunity in HCC.
  • To compare GITR expression on tumor-infiltrating lymphocytes (TIL) and blood leukocytes.
  • To evaluate combined GITR and PD-1 targeting effects on TIL.

Main Methods:

  • Assessed GITR expression on TIL, blood, and tumor-free liver leukocytes.
  • Used recombinant GITR-ligand and an anti-GITR antibody to stimulate TIL ex vivo.
  • Analyzed TIL proliferation, cytokine secretion (IFN-γ), and granzyme B production.
  • Compared single GITR or PD-1 targeting with combination therapy.

Main Results:

  • Regulatory T cells (Treg) showed higher GITR expression than effector T cells across tissues.
  • Highest GITR expression was on activated Treg within tumors.
  • GITR agonists enhanced TIL proliferation and effector functions (IFN-γ, granzyme B) against tumor antigens.
  • Combination therapy with anti-GITR and anti-PD1 (nivolumab) showed enhanced TIL responses in some patients.

Conclusions:

  • Agonistic GITR targeting boosts HCC TIL functionality.
  • GITR agonists represent a promising strategy for HCC immunotherapy, potentially in combination with PD-1 blockade.
Keywords:
CD357GITRHCCPD1TNFRSF18Tregcancer immunotherapy

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