Endocrine Side Effects Induced by Immune Checkpoint Inhibitors

Context: In recent years, progress has been made in cancer immunotherapy by the development of drugs acting as modulators of immune checkpoint proteins, such as the cytotoxic T-lymphocyte antigen-4 (CTLA4) andprogrammeddeath-1 (PD-1), two co-inhibitory receptors that are expressed on T cells upon activation. These molecules play crucial roles in maintaining immune homeostasis by down-regulating T-cell signaling, thereby preventing unbridled T-cell proliferationwhilemain-taining tolerance to self-antigens, such as tumor-associated antigens. CTLA4 blockade through systemic administration of the CTLA4-blocking antibody ipilimumab was shown to confer signif-icant survival benefit and prolonged stable disease in patients affected by advanced cutaneous melanoma. Other immune checkpoint inhibitors are under clinical evaluation. However, immune checkpoint blockade can lead to the breaking of immune self-tolerance, thereby inducing a novel syndromeof autoimmune/autoinflammatory side effects, designated as “immune-related adverse events, ” mainly including rash, colitis, hepatitis, and endocrinopathies. Data Acquisition: We searched the medical literature using the words “hypophysitis, ” “hypopi-tuitarism, ” “thyroid, ” “adrenal insufficiency, ” and “endocrine adverse events ” in associationwith “immune checkpoint inhibitors, ” “ipilimumab, ” “tremelimumab, ” “PD-1, ” and “PD-1-L.