Mechanisms and therapeutic strategies of immune checkpoint molecules and regulators in type 1 diabetes

Abstract

Background: Considered a significant risk to health and survival, type 1 diabetes (T1D) is a heterogeneous autoimmune disease characterized by hyperglycemia caused by an absolute deficiency of insulin, which is mainly due to the immune-mediated destruction of pancreatic beta cells.

Scope of review: In recent years, the role of immune checkpoints in the treatment of cancer has been increasingly recognized, but unfortunately, little attention has been paid to the significant role they play both in the development of secondary diabetes with immune checkpoint inhibitors and the treatment of T1D, such as cytotoxic T-lymphocyte antigen 4(CTLA-4), programmed cell death protein-1(PD-1), lymphocyte activation gene-3(LAG-3), programmed death ligand-1(PD-L1), and T-cell immunoglobulin mucin protein-3(TIM-3). Here, this review summarizes recent research on the role and mechanisms of diverse immune checkpoint molecules in mediating the development of T1D and their potential and theoretical basis for the prevention and treatment of diabetes.

Major conclusions: Immune checkpoint inhibitors related diabetes, similar to T1D, are severe endocrine toxicity induced with immune checkpoint inhibitors. Interestingly, numerous treatment measures show excellent efficacy for T1D via regulating diverse immune checkpoint molecules, including co-inhibitory and co-stimulatory molecules. Thus, targeting immune checkpoint molecules may exhibit potential for T1D treatment and improve clinical outcomes.

Keywords: immune checkpoint inhibitors; immune checkpoints; immunotherapy; lymphocyte; type 1 diabetes.

Figure 1

The regulatory roles of T cells in autoimmune reaction (created with Biorender).

Figure 2

The roles of the PD-1/PD-L1 pathway in ICI-induced T1D.

Figure 3

The treatment measures for T1D via regulating T cells. The blue rectangles represent co-inhibitory molecules while the yellow rectangles represent co-stimulatory molecules (created with Biorender).