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Published on: June 16, 2011
The Role of Programmed Death-1 in Type 1 Diabetes
Christopher G Tucker1, Alexander J Dwyer1, Brian T Fife2
1Department of Medicine, Center for Immunology, University of Minnesota Medical School, 2101 6th St SE, Wallin Medical Biosciences Building, 3-146, Minneapolis, MN, 55455, USA.
Purpose Of Review:
Programmed death-1 (PD-1) is an inhibitory receptor that controls T and B cell proliferation and function through interacting with its ligand PD-L1 or PD-L2. PD-1/PD-L1 blockade reboots anti-tumor immunity and is currently used to treat > 15 different types of cancer. However, the response rate is not at 100% and some patients relapse. Importantly, up to 37% of patients treated with PD-1/PD-L1 blocking antibodies develop immune-related adverse events, including overt autoimmunity, such as type 1 diabetes (T1D). Herein, we discuss the role of PD-1, PD-L1, and PD-L2 signaling in pre-clinical models of T1D, including recent work from our laboratory.
Recent Findings:
We highlight ongoing efforts to harness PD-1/PD-L1 signaling and treat autoimmunity. We also evaluate studies aimed at defining biomarkers that could reliably predict the development of immune-related adverse events after clinical PD-1/PD-L1 blockade. With increasing use of PD-1 blockade in the clinic, onset of autoimmunity is a growing health concern. In this review, we discuss what is known about the role of PD-1 pathway signaling in T1D and comment on ongoing efforts to identify patients at risk of T1D development after PD-1 pathway blockade.
Insights
Programmed death-1 (PD-1) blockade boosts anti-tumor immunity but can cause type 1 diabetes (T1D). This review explores PD-1 pathway roles in T1D and identifies at-risk patients for PD-1 blockade therapy.
Area of Science:
- Immunology
- Oncology
- Endocrinology
Background:
- Programmed death-1 (PD-1) is an inhibitory receptor regulating T and B cell functions via PD-L1/PD-L2 interactions.
- PD-1/PD-L1 blockade enhances anti-tumor immunity, approved for over 15 cancers, but response rates are suboptimal and relapse occurs.
- A significant concern is immune-related adverse events, including type 1 diabetes (T1D), affecting up to 37% of patients receiving PD-1/PD-L1 blockade.
Purpose of the Study:
- To review the role of PD-1, PD-L1, and PD-L2 signaling in pre-clinical type 1 diabetes (T1D) models.
- To discuss current strategies for utilizing PD-1/PD-L1 signaling to treat autoimmunity.
- To evaluate biomarkers for predicting immune-related adverse events following PD-1/PD-L1 blockade.
Main Methods:
- Review of pre-clinical models investigating PD-1 pathway signaling in type 1 diabetes.
- Analysis of studies focused on harnessing PD-1/PD-L1 signaling for autoimmune treatment.
- Evaluation of research identifying biomarkers for predicting adverse events.
Main Results:
- PD-1 pathway signaling plays a critical role in the pathogenesis of type 1 diabetes.
- Ongoing research aims to leverage PD-1/PD-L1 pathways for managing autoimmune conditions.
- Identifying predictive biomarkers for T1D development post-PD-1 blockade is crucial due to increasing clinical use.
Conclusions:
- Understanding PD-1 pathway's role in T1D is essential for managing immunotherapy side effects.
- Developing predictive biomarkers will enable safer application of PD-1 blockade in cancer patients.
- Further research is needed to balance anti-tumor efficacy with preventing autoimmune complications like T1D.
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