Patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) develop chronic mucocutaneous candidiasis during childhood and about 10% of senior patients develop upper GI tract squamous cell carcinoma (SCC), suggesting that C. albicans infection may be relevant to the cause of SCC development in APECED patients. In this study, we investigated the role of C. albicans infection in upper GI tract SCC development using an APECED-like IKKα kinase-dead (KA/KA) mouse model. We found that KA/KA mice developed upper GI tract SCC after oral infection of WT C. albicans weekly for three months. Interestingly, while upper GI tract SCC development in C. albicans - infected KA/KA mice is IL-17a-independent, EGFR pathway plays an important role in C. albicans infection-mediated tumorigenesis in KA/KA mice, as evidenced by significantly lower SCC incidence in the upper GI tract of KA/KA mice infected with Als3Δ/Δ C. albicans. Moreover, upper GI tract SCCs from WT C. albicans-infected KA/KA mice exhibited robust p-EGFR and Ki67 signals. However, both p-EGFR and Ki67 signals were only mildly increased in upper GI tract of Als3Δ/Δ C. albicans-infected KA/KA mice compared to WT control mice. Meanwhile, EGFR inhibition dramatically reduced C. albicans colonization in upper GI tract and the weight of stomach in KA/KA mice. Furthermore, we found that aberrant infiltrations of neutrophils and macrophages with significant inflammatory signatures were present in the upper GI tract SCCs in KA/KA mice. Interestingly, KA/KA neutrophils exhibited a defect in C. albicans killing capacity due to functional defects in ROS generation, degranulation, NETs formation, and apoptosis. We reasoned that KA/KA neutrophils’ inability in C. albicans killing capacity may further enhance the tumor-promoting microenvironment. Finally, whole genome sequencing data suggested that C. albicans infection may lead to genome instability. Currently we are investigating the role of neutrophil infiltration in C. albicans infection-mediated upper GI tract tumorigenesis.
Citation Format: Feng Zhu, Quynh T. Phan, Elise M. Ferre, Jami Willette-Brown, Rosalba Salcedo, Tsai-Wei Shen, Yu Fan, Yongmei Zhao, Monika Mehta, Daoud Meerzaman, Bao Tran, Giorgio Trinchieri, Michail S. Lionakis, Scott G. Filler, Yinling Hu. C. albicans infection mediates upper gastrointestinal tract malignancy independently of Il17a in an APECED-like mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3044.