Thyroid-related adverse events induced by immune checkpoint inhibitors

Abstract

Immune checkpoint inhibitors, namely anti-CTLA-4, anti-PD-1 and anti-PD-L1 monoclonal antibodies, have emerged in the last decade as a novel form of cancer treatment, promoting increased survival in patients. As they tamper with the immune response in order to destroy malignant cells, a new type of adverse reactions has emerged, known as immune-related adverse events (irAEs), which frequently target the endocrine system, especially the thyroid and hypophysis. Thyroid irAEs include hyperthyroidism, thyrotoxicosis, hypothyroidism and a possibly life-threatening condition known as the "thyroid storm". Early prediction of occurrence and detection of the thyroid irAEs should be a priority for the clinician, in order to avoid critical situations. Moreover, they are recently considered both a prognostic marker and a means of overseeing treatment response, since they indicate an efficient activation of the immune system. Therefore, a multidisciplinary approach including both oncologists and endocrinologists is recommended when immune checkpoint inhibitors are used in the clinic.

Keywords: CTLA-4; PD-1; PD-L1; cancer treatment; endocrine; immune checkpoint inhibitors; immune-related adverse events; thyroid.

Figure 1

The mechanisms of action for immune checkpoint inhibitors include the CTLA-4 pathway (on the left, panels (A) and (B)) and the PD-1/PD-L1 pathway (on the right, panels (C) and (D)). Normally, CTLA-4 is present on the surface of T-cells and by binding to its ligands, CD80 and CD86 (expressed on antigen-presenting cells), it exerts an inhibitory effect on the T-cell proliferation (A). Anti-CTLA-4 antibodies (a variety of ICIs) bind to CTLA-4 and block its inhibitory effects, stimulating T-cell proliferation (B). Similarly, T-cells express PD-1, which binds to its ligand, PD-L1, present on cancer cells, suppressing T-cell proliferation (C). Anti-PD-1 antibodies bind to PD-1 blocking its inhibitory effects and stimulating T-cell proliferation (D).

Figure 2

Organs suffering from immune-related adverse events after administration of immune checkpoint inhibitors.