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Updated: Jul 12, 2025

A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3
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ARF6-dependent endocytic trafficking of the Interferon-γ receptor drives adaptive immune resistance in cancer

Yinshen Wee1,2,3,4, Junhua Wang1,2,3, Emily C Wilson1,2

  • 1Department of Pathology, University of Utah, Salt Lake City, Utah.

Biorxiv : the Preprint Server for Biology
|October 24, 2023
PubMed

Insights

Cancer uses adaptive immune resistance (AIR) to evade T cells. This study reveals ADP-Ribosylation Factor 6 (ARF6) is key to this process, impacting cancer

Area of Science:

  • Immunology
  • Cancer Biology
  • Cell Biology

Background:

  • Adaptive immune resistance (AIR) allows tumors to evade CD8+ T cell elimination.
  • Immune checkpoint inhibitors targeting PD-1 and CTLA-4 focus on Interferon-gamma (IFNγ)-driven AIR.
  • Tumor cell-intrinsic cytokine signaling, initiated at the plasma membrane, suggests endomembrane trafficking regulates AIR.

Approach:

  • Investigated the role of the trafficking protein ADP-Ribosylation Factor 6 (ARF6) in IFNγ-driven AIR.
  • Examined ARF6's effect on Interferon-gamma Receptor (IFNγR) trafficking and signaling.
  • Assessed the impact of ARF6 loss on immune checkpoint blockade (ICB) resistance in murine melanoma models and patient tumors.

Key Points:

  • ARF6 is critical for IFNγ-driven AIR by preventing IFNγR lysosomal transport, thus increasing cell-surface IFNγR expression.
  • This augmentation enhances tumor-intrinsic IFNγ signaling and promotes immunosuppressive gene expression.
  • Loss of ARF6 confers resistance to ICB in a murine melanoma model.

Conclusions:

  • ARF6-dependent endomembrane trafficking of the IFNγ receptor is a novel mechanism of tumor immune escape.
  • Low ARF6 expression in patient tumors correlates with poor outcomes following ICB treatment.
  • Targeting ARF6-mediated trafficking presents a potential strategy to overcome adaptive immune resistance and improve ICB efficacy.

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