A mouse model of hypophysitis (induced by repeated injections of anti-CTLA-4 into C57BL/6 mice) resulted in lymphocytic infiltration into the pituitary gland and circulating anti-pituitary autoantibodies specific to thyrotropin-, gonadotropin-, and corticocotropin secreting cells.59 Interestingly, pituitary glands expressed CTLA-4 in a subset of these cells, which were targets for CTLA-4 antibody binding, and resulted in complement deposition. in 2011, immune checkpoint inhibitors (ICI) have rapidly become an integral part of many cancer therapeutic regimens. These novel drugs can markedly improve survival rates in several forms of cancer, but they can also induce a wide array of immune-related adverse events (irAEs) that can range from mild to life-threatening. Among the most common of these irAEs are the ICI-induced endorinopathies. Due to the the relatively vague nature of symptoms associated with these adverse events, timely diagnosis requires a high index of suspicion. Prompt recognition of the conditions and initiation of treatment can have dramatic effects on the patients health and quality of life. In this review, we discuss the general mechanisms and characteristics of ICI therapy and toxicities, followed by a specific review of the current state of the science regarding the epidemiology and pathophysiology of ICI-associated endocrinopathies. We also review the typical clinic presentation, recommended steps in screening, diagnosis, and management of these conditions. ICI mechanism of action ICI are monoclonal antibodies that are now widely used in cancer treatment.1 These agents are approved in 17 different cancer types and have emerged, alongside surgery, radiation, chemotherapy, and targeted therapy, as a fundamental pillar of cancer treatment. Approximately half of all metastatic cancer patients are now eligible for these treatments, with many more approvals and indications expected in the coming years.2 Effective combinations with dual ICI therapy, and regimens combined with targeted therapy and chemotherapy are now being widely used.3 Further, these agents Prkg1 are being used in the adjuvant or maintenance setting in melanoma, urothelial carcinoma, and non-small cell lung cancer, thus expanding their use to patients without active cancer. 4C6 ICI function primarily in two key signaling pathways related to T cell activation and exhaustion. A full discussion of these pathways is beyond the scope of this review, and is shown schematically in Figure 1.1 The first ICI approved was ipilimumab, a monoclonal antibody targeting cytotoxic T lymphocyte antigen-4 (CTLA-4). This signaling node functions largely in the context of antigen-presenting cell (APC) engaging with T cells in the periphery (lymph nodes) although additional functionality in the tumor microenvironment may also be relevant. The second pathway involves engagement between programmed cell death-1 and its ligand (PD-1/PD-L1). This interaction is relevant in the context of an inflamed tumor microenvironment as well as other chronic inflammatory settings. Open in a separate window Figure 1: Schematic of immune checkpoint inhibitor activity; anti-CTLA-4 (left) and anti-PD-1/PD-L1 (right). T cell activation requires 1) engagement of a T cell receptor (TCR) with an antigen presented in the context of a major histocompatibility complex (MHC), and 2) a second signal consisting of engagement of CD28 with B7. CTLA-4 opposes this second signal, by binding to B7 at higher affinity than CD28, thus limiting T cell activation. Blocking CTLA-4 pharmacologically, therefore removes the brakes on T cell activation and allows for unopposed engagement of the second signal. PD-1, a receptor on T cells, binds PD-L1, expressed on a variety of cells including tumor cells and tumor-infiltrating macrophages, which triggers a cascade of T cell inhibitor processes known as T cell exhaustion. Blocking either side of this interaction (with PD-1 or PD-L1 targeting antibodies) prevents this engagement, precludes T cell exhaustion, and permits anti-tumor activity ICI Clinical Activity Ipilimumab (anti-CTLA-4) was the first approved ICI, receiving approval in 2011. Substantial clinical activity was observed primarily in melanoma, producing approximately 15-20% response rates, with 20% long-term survival, persisting even 10 years beyond treatment.7 Nepicastat (free base) (SYN-117) Nepicastat (free base) (SYN-117) This contrasted markedly with the efficacy of chemotherapy and even most targeted therapies in solid tumors (which are usually associated with acquired resistance and temporary responses), and provided an important proof of principle for immunotherapy activity. More importantly, agents targeting PD-1 (nivolumab, pembrolizumab, cemiplimab) and PD-L1 (atezolizumab, avelumab, durvalumab) have demonstrated more widespread efficacy, now receiving approvals in 17 different cancer types, including cancers of the Nepicastat (free base) (SYN-117) skin, kidney, upper aeorodigestive tract, lung, head and neck, bladder, and many more. Response rates range from 15-25% (most solid tumors including lung cancers) to 40-60% (mismatch fix deficient malignancies and skin malignancies including melanoma) to 80-90% (Hodgkin Lymphoma).8 Several responses are durable, and could amount to a remedy in some sufferers although long run follow up is necessary. ICI-based combinations show great promise also. The mix of nivolumab and ipilimumab provides showed improved response prices in melanoma, lung cancers, renal cell carcinoma, and mismatch fix deficient cancer of the colon compared with one agent therapy, although at a price of elevated toxicities (find following section).9C11 Anti-PD-1/PD-L1 agents pared with chemotherapy have.