The Targets of Immune Adverse Events in Cancer Immunotherapy by Combined Check-point Inhibitors Resemble those Seen in IPEX Patients

Abstract

Introduction: Specific determinants of target-organ damage in autoimmune diseases are complex and multifactorial, several genetic and environmental factors are recognized but mostly remain unknown. Immunotherapy with "check-point inhibitors" (CPI) is complicated by immune related adverse events (IRAE), occurring in a large fraction of patients, with organ-specific inflammation of immunologic aetiology. We hypothesized that such IRAE are associated to regulatory T cell (Treg) dysfunction. To start testing this hypothesis, we have now compared organ targets of CPI-induced IRAE with those described in IPEX (Immune dysregulation polyendocrinopathy enteropathy X-linked) patients carriers of deleterious mutations in the Foxp3 gene leading to deficient/absent Treg. METHOD: We compared the frequency of autoimmune diseases (AID) in three groups of conditions: CPI-induced IRAE, IPEX patients, and the General Population (GP) through a PubMed search from 01/01/1998 to 31/05/2024. For each group, and each autoimmune disease, the highest reported frequency was selected, listed in reference to CPI-IRAE and classified from the highest to lowest prevalence. Identified were enteropathy, rash (eczema or other dermatitis), transaminitis/hepatitis, hypothyroidism, increased lipase/exocrine pancreatitis, arthralgia/inflammatory arthritis, hypophysitis, adrenal insufficiency, type 1 diabetes mellitus, haemolytic anaemia, Sjögren´s syndrome, polymyalgia rheumatica, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis and systemic sclerosis. RESULTS: While dermatitis and thyroid disease are also the most frequent AID in the GP, the latter, together with enteropathy, hepatitis, and adrenal insufficiency are much more frequent in CPI-IRAE and IPEX. Of note, the most frequent systemic AID in the GP such as de novo Sjögren´s syndrome, polymyalgia rheumatica, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis and systemic sclerosis are extremely rare in CPI-IRAE (few case reports) and not described in IPEX.

Conclusion: Our finding provides further evidence for the possibility that the functional inhibition/inactivation of Treg is a plausible contributing mechanism in the physiopathology of CPI-IRAE.

Keywords: Cancer immunotherapy; Check-point inhibitors; IPEX; Immune-related adverse events; Regulatory T cells.