Abstract 6674: Fungi utilizes exocytosis pathway to facilitate the release of DAMPs from pancreatic cancer cells

Abstract

Abstract Recent studies overwhelmingly show that microbiome is pervasive to tumor and play key role in immunotherapy response and reprograming tumor immune microenvironment (TIME). However, it remains unknown how microbiome facilitates the host-immune cell crosstalk and promote tumorigenesis. Our recent study in pancreatic ductal adenocarcinoma (PDAC) show that intratumor fungal microbiome facilitate the release of a damage associated molecular pattern (DAMP) molecule IL-33 from cancer cells. The secreted IL33 from cancer cells in turns recruits ILC2 and TH2 cells which promotes PDAC tumorigenesis. However, the mechanism of fungal mediated IL-33 release from PDAC cells remains unknown. Our follow up studies using high throughput integrated proteomic profiling and immunoprecipitation revealed a group of exocyst complex proteins interacting with IL-33 in the presence of fungus. The exocyst complex consists of eight sub-unit proteins that tethers the secretory vesicles to the plasma membrane and implicated in cellular exocytosis. We found EXOC6B a component of exocyst complex, modulates IL-33 release via exocytosis pathway from the PDAC cells. Genetic depletion of EXOC6B resulted in shunted IL-33 release and significantly abrogated PDAC tumor progression. Mechanistically, we found that mycobiome activates a non-canonical TLR2-CARD9 pathway, thereby driving IL-33 nucleocytoplasmic transport and exocytosis. This study identifies a unique mechanism of EXOC6B mediated release of IL-33 that expands our knowledge on how host-mycobiome interaction shapes PDAC tumor microenvironment by intricate molecular mechanism. Our study identifies EXOC6B as a new therapeutics target involved in the mycobiome driven IL-33 secretion in pancreatic cancer. Citation Format: Aftab Alam, Shyamananda Singh Mayengbam, Sharon Senchanthisai, Bektas Irmak, Prasenjit Dey. Fungi utilizes exocytosis pathway to facilitate the release of DAMPs from pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6674.