Immune checkpoint inhibitor diabetes mellitus: a novel form of autoimmune diabetes

Abstract

Autoimmune diabetes mellitus is a rare but significant side effect of treatment with immune checkpoint inhibitors. Immune checkpoint inhibitor-induced diabetes mellitus (CPI-DM) is characterized by acute onset of dramatic hyperglycemia with severe insulin deficiency and occurrence following exposure to programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors rather than cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors. As a growing number of patients undergo immunotherapy, further understanding of the characteristics of CPI-DM patients is needed for improved prognostic and diagnostic application in order to reduce overall morbidity for this already at-risk population. Additionally, understanding of the features and mechanisms of CPI-DM may contribute to understanding mechanisms of spontaneous type I diabetes mellitus (T1DM). Here, we summarize the clinical features of CPI-DM and interrogate the genetic and cellular mechanisms that may contribute to the disease, as well as the clinical challenges for predicting and treating these patients as increasing cancer immunotherapies reach clinical utility.

Keywords: autoimmune diabetes mellitus; immune checkpoint inhibitor; immune-related adverse event.

Figure 1

Immune Checkpoints and Immune Checkpoint Inhibitors (a) In the lymph node, naïve T cells are activated by a two signal system. The MHC complex on an antigen presenting cell (APC) presents antigen to the T cell receptor (TCR) on the naïve T cell. Costimulation via CD80 or CD86 on the APC binding to CD28 on the naïve T cell then leads to T cell activation. (b) In the lymph node, the presence of CTLA‐4 expression on either the naive T cell or regulatory T cells (Treg) prevents binding of CD80 or CD86 on the APC to CD28 on the T cell, thereby effectively inhibiting the immune response. In the periphery, the presence of PD‐L1 on the tumor leads to inhibition of effector T cells. (c) Immune checkpoint inhibitors prevent inhibition of the immune response. CTLA‐4 inhibitors act in the lymph tissues by blocking CTLA‐4, thereby allowing the second signal for activation of naïve T cells via CD28. At the tumor, PD‐1 inhibitors bind to PD‐1 expressed on the effector T cells and PD‐L1 inhibitors bind to PD‐L1 expressed by the tumor; this allows for activation of the immune response.

Figure 2

Hypothesized Mechanism for CPI‐DM. Genetic predisposition is likely to play a role in development of CPI‐DM. In individuals with a genetic predisposition, there are likely two components that are required. First, some unknown trigger that leads to b cell stress and priming of an immune response through PD‐L1 expression on the b cell along with recruitment of CD8+ T cells and APCs to the pancreas. Second, exposure to a PD‐1/ PD‐L1 inhibitor likely reinvigorates exhausted CD 8+ T cells. It is likely that these events may occur in either order. Once these two events have occurred, b cells fall victim to primed CD 8+ T cells.