Faculty, Staff and Student Publications
Publication Date
2-14-2022
Journal
Cancer Cell
Abstract
TH2 cells and innate lymphoid cells 2 (ILC2) can stimulate tumor growth by secreting pro-tumorigenic cytokines such as interleukin-4 (IL-4), IL-5, and IL-13. However, the mechanisms by which type 2 immune cells traffic to the tumor microenvironment are unknown. Here, we show that oncogenic KrasG12D increases IL-33 expression in pancreatic ductal adenocarcinoma (PDAC) cells, which recruits and activates TH2 and ILC2 cells. Correspondingly, cancer-cell-specific deletion of IL-33 reduces TH2 and ILC2 recruitment and promotes tumor regression. Unexpectedly, IL-33 secretion is dependent on the intratumoral fungal mycobiome. Genetic deletion of IL-33 or anti-fungal treatment decreases TH2 and ILC2 infiltration and increases survival. Consistently, high IL-33 expression is observed in approximately 20% of human PDAC, and expression is mainly restricted to cancer cells. These data expand our knowledge of the mechanisms driving PDAC tumor progression and identify therapeutically targetable pathways involving intratumoral mycobiome-driven secretion of IL-33.
Keywords
Animals, Biomarkers, Disease Models, Animal, Disease Progression, Disease Susceptibility, Gene Expression Regulation, Neoplastic, Humans, Immunity, Innate, Immunophenotyping, Interleukin-33, Lymphocyte Count, Lymphocytes, Tumor-Infiltrating, Mice, Models, Biological, Mycobiome, Pancreatic Neoplasms, Prognosis, T-Lymphocyte Subsets, Tumor Microenvironment, Type 2 immune response, cytokines, innate lymphoid cells (ILC2), TH2, fungal mycobiome, Kras, PDAC
DOI
10.1016/j.ccell.2022.01.003
PMID
35120601
PMCID
PMC8847236
PubMedCentral® Posted Date
2-14-2023
PubMedCentral® Full Text Version
Author MSS
Graphical Abstract
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons