Related Experiment Video
Updated: May 30, 2025
Investigating Target Gene Function in a CD40 Agonistic Antibody-induced Colitis Model using CRISPR/Cas9-based Technologies
Published on: June 2, 2021
A mouse model to assess immunotherapy-related colitis
Yaiza Senent1, Ana Remírez2, Beatriz Tavira3
1Laboratory of Translational Oncology, Program in Solid Tumors, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain; Department of Biochemistry and Genetics, School of Sciences, Universidad de Navarra, Pamplona, Spain; Navarra's Health Research Institute (IDISNA), Pamplona, Spain.
Abstract:
Combined blockade of the immune checkpoints PD-1 and CTLA-4 has shown remarkable efficacy in patients with melanoma, renal cell carcinoma, non-small-cell lung cancer and mesothelioma, among other tumor types. However, a proportion of patients suffer from serious immune-related adverse events (irAEs). In severe cases, a reduction of the doses or the complete cessation of the treatment is required, limiting the antitumor efficacy of these treatments. Colitis is among the most frequent and problematic irAE associated with immune checkpoint blockade. In this context, animal models that recapitulate the pathophysiological features of immunotherapy-related colitis are needed. In this manuscript, we describe our experience with a mouse model in which the combined CTLA-4 and PD-1 blockade exacerbates the deleterious effects of dextran sulfate sodium (DSS)-induced colitis. This model may constitute a valuable tool for the study of immunotherapy-related colitis.
Insights
Combined PD-1 and CTLA-4 blockade shows efficacy but causes severe immune-related adverse events (irAEs), particularly colitis. This study presents a novel mouse model to better study immunotherapy-induced colitis, aiding future research and treatment strategies.
Area of Science:
- Immunology
- Oncology
- Gastroenterology
Background:
- Combined blockade of PD-1 and CTLA-4 immune checkpoints demonstrates significant efficacy across various cancers.
- Immune-related adverse events (irAEs), especially colitis, are a significant challenge, often necessitating treatment cessation and limiting therapeutic potential.
Purpose of the Study:
- To develop and validate a mouse model that accurately recapitulates the key features of immunotherapy-related colitis.
- To provide a preclinical tool for investigating the mechanisms underlying colitis induced by combined immune checkpoint blockade.
Main Methods:
- Utilized a mouse model subjected to combined CTLA-4 and PD-1 blockade.
- Induced colitis using dextran sulfate sodium (DSS).
- Assessed the exacerbation of DSS-induced colitis by combined immune checkpoint blockade.
Main Results:
- Combined CTLA-4 and PD-1 blockade significantly worsened the effects of DSS-induced colitis in the mouse model.
- The model demonstrated key pathophysiological features relevant to human immunotherapy-related colitis.
Conclusions:
- The developed mouse model serves as a valuable preclinical tool for studying immunotherapy-related colitis.
- This model can facilitate research into the mechanisms and potential therapeutic interventions for colitis associated with immune checkpoint inhibitors.
