Cancer immunotherapy - immune checkpoint blockade and associated endocrinopathies

Abstract

Advances in cancer therapy in the past few years include the development of medications that modulate immune checkpoint proteins. Cytotoxic T-lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) are two co-inhibitory receptors that are expressed on activated T cells against which therapeutic blocking antibodies have reached routine clinical use. Immune checkpoint blockade can induce inflammatory adverse effects, termed immune-related adverse events (IRAEs), which resemble autoimmune disease. In this Review, we describe the current data regarding immune-related endocrinopathies, including hypophysitis, thyroid dysfunction and diabetes mellitus. We discuss the clinical management of these endocrinopathies within the context of our current understanding of the mechanisms of IRAEs.

Figure 1

A. Normal CTLA4 interaction with B7 costimulatory ligand. 1) First activation signal is initiated when T-cell receptor (TCR) binds to antigen presenting cell’s (APC) MHC presenting an antigen. 2) Second activation signal is fired when CD28 receptor binds to B7 costimulatory ligand on the APC. 3) CTLA4 receptors present on T-cell act as a checkpoint, and inhibits T-cell activation by outcompeting CD28 receptors to bind to B7 ligand. This negates the effect of second activation signal. B. Ipilimumab, an anti-CTLA4 antibody, indirectly increases T-cell activity by binding to the CTLA4 receptor. Second activation signal via B7 and CD28 connection is reactivated. C. By blocking either PD-1 or PD-L1 protein, Nivolumab enables the T-cell to detect tumor cells. D. By blocking either PD-1 or PD-L1 protein, Nivolumab enables the T-cell to detect tumor cells.

Figure 2

Pituitary tissues express ectopic CTLA4 protein. Binding to CTLA4 autoantibodies or Ipilimumab IgG1 is thought to lead to activation of classical complement pathway.