Fungal Infection and Immune Dysfunction Contribute to Esophageal Carcinogenesis

Authors

• F Zhu
• J Willette-Brown
• NY Song
• D Lomada
• Y Song
• L Xue
• Z Gray
• SR Davis
• ZH Sun
• PL Zhang
• XL Wu
• QM Zhan
• ER Richie
• YL Hu

Abstract

Human esophageal cancer is the sixth leading cause of cancer death worldwide. More than 90% of esophageal cancer is esophageal squamous cell carcinoma (ESCC). While the etiological cause remains unclear, esophageal mucosal fungal infection is very common in esophageal cancer patients, including patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) who have more than 20-fold risk of ESCC when compared to the healthy population. Here, we report that kinase-dead Ikka knock-in mice (hereafter referred to as mutant mice) develop APECED-like autoimmune disease due to developmental defects in thymus and lack of central tolerance. Similar to human APECED patients who develop esophageal mucosal fungal infection on average at the age of five, mutant mice develop fungal infection in oral cavity and esophagus as early as seven weeks old. About 20% of mutant mice develop ESCC during aging, which exhibits specific molecular signatures observed in human ESCC, such as p16 gene silencing, elevated EGFR phosphorylation and PD-L1 expression, etc. Autoreactive T cell depletion, or central tolerance reconstitution and/or normal T cell transfer prevents fungal infection and ESCC development in mutant mice. Importantly, antifungal drug treatment inhibits inflammation and ESCC development in mutant mice. However, oral inoculation of Clasdosporium, one of the major fungal species isolated from mutant mice, increases the tumor incidence from 20% to 63% in mutant mice. These results reveal that immune dysfunction and fungal infection is associated with ESCC development, which sheds new light on ESCC etiological factors, prevention and treatment.

Scientific Focus Area: Cancer Biology

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