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ISG15/GRAIL1/CD3 axis influences survival of patients with esophageal adenocarcinoma
Dyke P McEwen1, Paramita Ray2, Derek J Nancarrow1
1Department of Surgery, Section of Thoracic Surgery.
JCI Insight
|May 23, 2024
Summary
A new pathway involving ISG15 and GRAIL1 degrades CD3, reducing T cell activity and worsening survival in esophageal adenocarcinoma (EAC). This immunosuppression mechanism offers potential therapeutic targets for EAC patients.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Esophageal adenocarcinoma (EAC) is characterized by immunosuppression, correlating with poor overall survival (OS).
- Upstream factors potentially influencing T cell activity and CD3 levels may drive EAC immunosuppression and survival outcomes.
Purpose of the Study:
- To investigate a pathway impacting CD3 protein stability and T cell activity in EAC.
- To identify molecular mechanisms contributing to immunosuppression and poor survival in EAC.
Main Methods:
- Analysis of clinical data and patient samples from Barrett's esophagus to EAC progression.
- Gene expression (RNA-Seq) and protein expression (tissue microarray) analysis.
- Cell biology studies to delineate the CD3 degradation pathway.
Main Results:
- Loss of CD3-ε expression and reduced CD3+ T cells correlated with worse OS in EAC.
- The GRAIL1 isoform degraded CD3 proteins and inactivated T cells, while GRAIL2 stabilized them.
- Interferon-stimulated gene 15 (ISG15) facilitated GRAIL1-mediated CD3 degradation.
Conclusions:
- An ISG15/GRAIL1/mutant p53 amplification loop negatively impacts CD3 levels and T cell activity.
- This pathway promotes immunosuppression in esophageal adenocarcinoma.
- Targeting this loop may offer therapeutic strategies for EAC.
