Autoimmune type 1 diabetes and immune checkpoint inhibitors
المؤلف:
Holt, Richard IG, and Allan Flyvbjerg
المصدر:
Textbook of diabetes (2024)
الجزء والصفحة:
6th ed , page218-219
2025-11-16
24
The host immune system plays a key role in biological surveillance and defence against external and internal stressors. Among the many immune mediators, there is cross- talk between CTL and Treg lymphocytes, which results in the release of various pro- inflammatory and anti- inflammatory cytokines in response to different antigens. Although a full review of the subject is beyond the scope of this chapter, dysregulation of this immune- modulating system may result in a spectrum of conditions including chronic infection, autoimmunity, and cancer. Chronic stimulation of CTL could lead to progressive loss of cytokine production and cytotoxicity, so called T- cell exhaustion, which might promote cancer development and chronic viral infection with reduced clearance of viral load. In contrast, continuing activity of autoreactive cytotoxic cells could mediate the destruction of host tissues resulting in autoimmune diseases. The immune checkpoints, PD- 1 receptor and its ligand PDL- 1, are immunoreceptors widely expressed in many tis sues. They form part of the feedback of the cytotoxic pathway to reduce the risk of autoimmunity. Thus, while PD- 1 agonists have been used to suppress adverse immune responses for the treatment of autoimmune diseases, allergy, and transplant rejection, PD- 1 inhibitors have been used to augment the immune response for treatment of cancer and infectious diseases.
Since the introduction of PD- 1 and PDL- 1 inhibitors as immune- checkpoint inhibitors for treating multiple types of cancer, there have been increasing numbers of case reports of autoimmune dis ease as a drug- related adverse reaction. A recent systematic review and meta- analysis summarized the clinical course of 71 individuals presenting with type 1 diabetes after the initiation of immune- checkpoint inhibitor therapy. The mean age of these individuals was 61.7 years, with 55% being men and melanoma being the most frequent cancer (53.5%). Other cancer types included lung, head and neck, renal cell, and urothelial carcinoma. The median time to onset of type 1 diabetes was 49 days, with DKA presentation in 76% of the individuals. The mean HbA1c was 7.8% (62 mmol/mol) at presentation. All individuals had insulin deficiency and required permanent exogenous insulin treatment, with half of the individuals having autoantibodies associated with type 1 diabetes. These latter individuals had more rapid onset and higher incidence of DKA than those without auto- antibodies.
There are close associations among diabetes, cancer, and chronic infection, with type 1 diabetes being rare and type 2 diabetes and cancer being common in non- Europid populations living in areas endemic for low- grade infections. These intriguing observations associated with autoimmunity and immune- checkpoint inhibitors should motivate more studies to examine the interplay among these immune- modulating pathways in both type 1 diabetes and type 2 diabetes and their associated aetiologies (e.g. acute or chronic infections) as well as subphenotypes (e.g. cancer and auto immune disease). From a clinical practice perspective, the increasing use of immune- checkpoint inhibitors in different cancer conditions should alert healthcare professionals regarding this potential drug- related severe adverse event in the context of diabetes.
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