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Mouse models of immune-related adverse events: progress, challenges, and opportunities
Theodoros Papadopoulos1, Ariel Pinto1, Madelyn J Abraham2
1Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada; Division of Clinical and Translational Research, McGill University, Montreal, Quebec, Canada.
Abstract:
With immune checkpoint inhibitors (ICIs) being an established therapeutic pillar for many cancers, the management of their associated toxicities has emerged as a key clinical challenge. Immune-related adverse events (irAEs) frequently require immunosuppressive therapy, raising the concern that these treatments may dampen the antitumor effects elicited by ICIs. Foundational work in mice enabled the discovery of ICIs, and in this review, we discuss the continued importance of preclinical mouse modeling to understand the molecular mechanisms underpinning the most common irAEs. Mouse models can be used as surrogates to evaluate the effects of immunosuppressive therapies on irAEs, tumor growth, and ICI-mediated antitumor immunity. In reviewing genetic and pharmacological approaches to induce irAEs in mice, we identify key considerations for developing next-generation mouse models of irAEs.
Insights
Immune checkpoint inhibitors (ICIs) treat cancer but can cause toxicities. Preclinical mouse models are crucial for understanding and managing these immune-related adverse events (irAEs) without compromising cancer treatment efficacy.
Area of Science:
- Immunology
- Oncology
- Preclinical Research
Background:
- Immune checkpoint inhibitors (ICIs) are vital cancer therapies.
- Managing toxicities like immune-related adverse events (irAEs) is a clinical challenge.
- Immunosuppressive treatments for irAEs may reduce ICI efficacy.
Purpose of the Study:
- To review the role of preclinical mouse models in understanding irAEs.
- To evaluate how mouse models can assess immunosuppressive therapies' impact on irAEs and antitumor immunity.
- To identify considerations for developing advanced mouse models of irAEs.
Main Methods:
- Review of existing literature on mouse models for irAEs.
- Analysis of genetic and pharmacological methods to induce irAEs in mice.
- Evaluation of mouse models as surrogates for clinical scenarios.
Main Results:
- Mouse models are essential for dissecting irAE mechanisms.
- These models can predict the effects of immunosuppression on irAEs and anti-tumor responses.
- Key considerations for next-generation irAE mouse models were identified.
Conclusions:
- Preclinical mouse models are indispensable for managing ICI-related toxicities.
- Developing sophisticated mouse models is critical for optimizing cancer immunotherapy.
- Understanding irAEs in mice informs clinical management strategies.
