Severe autoimmunity after checkpoint inhibitor therapy in a patient with autoimmune polyglandular syndrome type 1

Immune checkpoint inhibitor (ICI) cancer therapies targeting programmed cell death protein 1 and cytotoxic T-lymphocyte-associated protein 4 enhance antitumor immunity in many cancers. Despite its efficacy, ICI therapy can trigger severe autoimmune attacks across various organ systems, termed immune-related adverse events (irAEs). Antitumor immunity and autoimmunity are tightly linked as demonstrated by the enhanced efficacy of ICI therapy in patients who develop irAEs. Whether patients with preexisting autoimmunity or genetic risk factors for autoimmunity should be offered ICI therapies remains uncertain. We present the case of a patient with autoimmune polyglandular syndrome type 1, caused by a pathogenic autoimmune regulator (AIRE) missense mutation, who was treated with ICI therapy for squamous cell carcinoma of the hard palate. She subsequently developed 3 concurrent irAEs: ICI-hepatitis, ICI-thyroiditis, and ICI-diabetes mellitus. For these irAEs, the patient was treated with immunosuppressants, thyroid hormone replacement, and basal bolus insulin therapy. This case highlights the need for careful evaluation of patients for underlying autoimmune diseases prior to ICI therapy initiation. It also highlights a 2-hit model wherein any impaired central immune tolerance combined with ICI therapy may predispose patients to multiple severe irAEs.