Exocyst complex regulates fungal-mediated IL-33 release and facilitates type 2 immune response 2304790

Abstract Introduction Recent studies overwhelmingly show that the fungal microbiome (mycobiome) is pervasive in tumors and plays a key role in reprogramming the tumor microenvironment. However, the molecular mechanism of fungal-mediated tumorigenesis remains unknown. Our recent study on pancreatic ductal adenocarcinoma (PDAC) shows that the intratumoral fungal mycobiome facilitates IL33 release from PDAC cells, thereby promoting PDAC tumorigenesis. However, the mechanism by which fungal infection mediates IL-33 release from PDAC cells remains unknown. Methods We used proteomic profiling, immunological techniques, orthotopic and genetically modified animal models, histology of human PDAC tissue microarray, and comprehensive molecular biology methods to identify the IL-33 secretion machinery and its role in PDAC progression. Results A high-throughput integrated proteomic profiling and protein-protein interaction study identified an Exocyst protein complex interacting with IL-33 in PDAC cells. The Exocyst complex consists of eight subunit proteins that tether the secretory vesicles to the plasma membrane and are implicated in cellular exocytosis. Further screening identified EXOC6B, a component of the Exocyst protein complex, which modulates IL-33 release via the exocytosis pathway from the PDAC cells. Genetic depletion of EXOC6B blocked IL-33 release and significantly abrogated PDAC tumor progression by suppressing type 2 immune response. Mechanistically, fungal mycobiome activates a non-canonical exocytosis pathway, thereby driving IL-33 nucleocytoplasmic transport and secretion from PDAC cells. Conclusion This study provides insights into a previously unrecognized mechanism and pathway of IL-33 release. Moreover, our findings bear important implications for identifying new therapeutic targets in various pathophysiological conditions, such as allergic airway disease and cancer, wherein fungal infections are known to increase IL-33 release and exacerbate the disease process. Funding Source Roswell Park Alliance foundation Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)