Autoreactive T Cells and Chronic Fungal Infection Drive Esophageal Carcinogenesis

Abstract

Humans with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a Tcell-driven autoimmune disease caused by impaired central tolerance, are susceptible to chronic fungal infection and esophageal squamous cell carcinoma (ESCC). However, the relationship between autoreactive Tcells and chronic fungal infection in ESCC development remains unclear. We find that kinase-dead Ikkα knockin mice develop APECED-like phenotypes, including impaired central tolerance, autoreactive Tcells, chronic fungal infection, and ESCCs expressing specific human ESCC markers. Using this model, we investigated the link between ESCC and fungal infection. Autoreactive CD4 Tcells permit fungal infection and incite tissue injury and inflammation. Antifungal treatment or autoreactive CD4 Tcell depletion rescues, whereas oral fungal administration promotes, ESCC development. Inhibition of inflammation or epidermal growth factor receptor (EGFR) activity decreases fungal burden. Fungal infection is highly associated with ESCCs in non-autoimmune human patients. Therefore, autoreactive Tcells and chronic fungal infection, fostered by inflammation and epithelial injury, promote ESCC development.