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Liver metastases dampen IL18-driven γδ T cell activity and immunotherapy responsiveness in colorectal cancer

Allard W J van Renterghem1, Miguel Parra-Martinez1, Maartje Witsen1

  • 1Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Oncode Institute, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.

Cell Reports. Medicine
|January 27, 2026
PubMed

Insights

Patients with liver metastases (LMs) benefit less from immune checkpoint blockade (ICB). This study reveals the IL18/IL18BP/Vδ1+ T cell axis is a key regulator of ICB response in mismatch repair-deficient (MMR-d) cancers with LMs.

Area of Science:

  • Immunology
  • Oncology
  • Cancer Research

Background:

  • Immune checkpoint blockade (ICB) efficacy is limited in patients with liver metastases (LMs).
  • The underlying mechanisms for reduced ICB benefit in LMs are not well understood.
  • Vδ1+ γδ T cells are reduced in the liver tumor microenvironment of mismatch repair-deficient (MMR-d) cancers treated with immunotherapy.

Purpose of the Study:

  • To investigate the role of the IL18/IL18BP/Vδ1+ T cell axis in ICB response in patients with LMs.
  • To identify mechanisms contributing to ICB resistance in liver metastases.
  • To explore potential therapeutic vulnerabilities in MMR-d cancers with LMs.

Main Methods:

  • Analysis of Vδ1+ γδ T cell populations and cytokine levels (IFNγ, IL18) in patients with LMs.
  • Ex vivo stimulation of liver γδ T cells with IL18.
  • In vitro assessment of IL18BP blockade on anti-tumor immunity using organoids.

Main Results:

  • Hepatic Vδ1+ T cells exhibit high baseline IFNγ production.
  • Elevated systemic IL18 levels in patients with LMs correlate with ICB success.
  • Liver γδ T cells are sensitive to IL18, but cancer cells secrete IL18BP to inhibit immunity.
  • IL18BP blockade enhances IFNγ-driven immunity against liver cancer organoids.

Conclusions:

  • The IL18/IL18BP/Vδ1+ T cell axis is a critical regulator of ICB response in MMR-d cancers with LMs.
  • Targeting IL18BP represents a potential therapeutic strategy to improve ICB efficacy in patients with liver metastases.
  • Understanding this axis offers insights into overcoming ICB resistance in specific cancer types.
Keywords:
IL18IL18bpcolorectal cancergamma delta T cellshepatic toleranceimmunotherapyinnate lymphocyteliver metastases

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