Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, the five-year survival rate of PDAC patient is around ten percent. It is fourth largest cause of cancer related death and is projected to become the second deadliest cancer by 2030. PDAC patients generally present with advanced stage, metastatic disease that is mostly resistant to chemotherapy, radiation, and immunotherapy. A significant finding is that mutant KrasG12D (Kras*) is the primary oncogenic driver of PDAC development, and therefore efforts have been devoted to target KRAS. Here, we show in pancreatic ductal adenocarcinoma (PDAC), oncogenic KrasG12D (Kras*) increases the expression of IL33, a damage-associated molecular pattern (DAMP) molecule, member of IL1 cytokine family protein and localized in the PDAC cell nucleus, which upon secretion, chemoattracts the type 2 immunocytes. Type 2 immune cells—TH2, eosinophils and innate lymphoid cells (ILC)2, stimulate tumor growth by secreting pro-tumorigenic cytokines such as IL4, IL5 and IL13. However, the mechanisms by which type 2 immune cells traffic to the tumor microenvironment (TME) are unknown. Cancer cell-specific deletion of IL33 leads to a significant reduction in TH2 and ILC2 recruitment and lead to tumor regression. Further, we discovered that the release of IL33 requires interactions between cancer cells and the intratumoral mycobiome. PDA tumors harbors a ~3000-fold higher fungal load compared to normal pancreas in both mouse and humans. However, the mechanism of fungal mediated cytokine release is still unknown and represents a target for limiting IL33 release, and lessening PDAC tumor burden. Genetic deletion of IL33 alone or fungal depletion leads to a decrease in TH2 and ILC2 infiltration along with robust tumor regression. Moreover, repopulation of the PDAC TME with fungal species such as Alternaria and Malassezia lead to a re-infiltration of type 2 immunocytes that reinvigorates tumor growth. Notably, transplantation of tumor-derived ILC2s into mice accelerates PDAC growth. Mechanistically fungus activates dectin-1 pathway in PDAC cancer cells, mediating the release of IL33. Consistent with the murine data, IL33 expression is upregulated in approximately 20% of human PDAC, which is mainly restricted to cancer cells. Collectively, our work shows that the intratumoral mycobiome stimulates PDAC to secrete IL33, which plays a leading role in facilitating the recruitment of type 2 immunocytes that promote tumor progression.

Citation Format: Aftab Alam, Eric Levanduski, Maulasri Bhatta, Sharon Senchanthisai, Sheila Jani Sait, Jianmin Wang, Scott I. Abrams I. Abrams, Prasenjit Dey. KRAS and fungi cooperate to drive IL33 secretion and type 2 immunity in the pancreatic cancer tumor microenvironment [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 2119.