Autoreactive T Cells and Chronic Fungal Infection Drive Esophageal Carcinogenesis

Abstract

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

Integrity of IKK/NF‐κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis

“…[7,9,10] Alternatively, IKKα suppresses carcinogenesis in the skin, lungs, esophagi, nasopharynges, and pancreas of humans and mice independently of canonical and noncanonical NF-kB pathways ( Figure 1B). [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] These findings highlight the medical importance of IKK/NF-kB in the pathogenesis of human diseases and malignancies.…”

“…Furthermore, in Ikkα KA/KA mice, IKKα inactivation impairs LTβR-, CD40-, or RANK-mediated canonical and noncanonical NF-kB activities in mTECs, resulting in significantly reduced mTEC numbers and downregulated Aire expression. [25] The reintroduction of IKKα in mTECs elevates NF-kB activities, Aire expression, and mTEC numbers and abolishes autoimmune phenotypes in Ikkα KA/KA mice ( Figure 2). mTEC is required for selecting T-cell repertoires.…”

“…[1,13,14,[48][49][50] The thymus of Ikkα À/À newborns show reduced medullary regions and mTEC numbers. [35,36] Transplantation of Ikkα À/À thymuses to the kidney of nude mice only causes lymphocyte infiltration in the liver and pancreas, [36] suggesting that solely thymic epithelial-cell phenotypes are insufficient to elicit a severe systemic autoimmune disease, such as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) [25,30,51] -like disease in mice. Furthermore, in Ikkα KA/KA mice, IKKα inactivation impairs LTβR-, CD40-, or RANK-mediated canonical and noncanonical NF-kB activities in mTECs, resulting in significantly reduced mTEC numbers and downregulated Aire expression.…”

“…Severe autoimmunity and systemic autoinflammation Tumors in the esophagus and oral cavity/ fungal infection [25,35,36] Skin, lung, esophgeal, oral, and pancreatic cancer [15][16][17][18][19][20][21][22][23][24][25][26][27][28] www.advancedsciencenews.com www.bioessays-journal.com NF-kB pathways. [1,13,14,[48][49][50] The thymus of Ikkα À/À newborns show reduced medullary regions and mTEC numbers.…”

“…Canonical and noncanonical NF-kB molecules and their regulators IKKα, IKKβ, NIK, and TRAF6 are required for mTEC development through CD40, RANK, and LTβR of the TNFR family receptors ( Table 1). [25,[31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] Notably, excepting IKKα, mice deficient in these molecules develop impaired central tolerance-associated autoimmune diseases, but they do not display manifestations with increased fungal infection and carcinogenesis.…”