Functions of IKK alpha in Skin Homeostasis and Skin Tumorigenesis

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

It is yet unknown how the interaction of fungus, tumors, and immune cells affects tumorigenesis. We uncovered that the enhanced STAT3-dependent oral squamous cell carcinoma (SCC) development by oral Cladosporium cladosporioides infection promoted the fungal growth whereas infection was cleaned up in wild-type mice, suggesting a synergic tumor-fungus loop involved in this accelerated carcinogenesis. Oral acidic metabolites elicited by C. cladosporioides infection were found to convert protective neutrophils to inflammatory neutrophils characterized by elevated IL-1b and decreased ROS, that failed to kill fungi. Such a neutrophil population expressing IL1B associated with fungi was identified in human head and neck SCCs (HNSCCs). Importantly, fungal counts were much greater in HNSCCs and SCC-adjacent tissues than in healthy controls, and the advanced HNSCCs had significantly increased fungal signals. A Firmicutes to Protobacteria change and enhanced bacterial numbers, which were also mediated by a C. cladosporioides-dependent oral acidic tumor milieu in mice, were detected in HNSCC patients showing poor survival. C. cladosporioides and induced IL-1b/IL-17A augmented STAT3 activity in SCC cells, contributing to local and distal skin tumorigenesis. Collectively, these traits shared between fungus-associated HNSCCs in humans and mice highlight that oral fungal infection constitutes the tumor microenvironment for tumor progression.