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.
Original language | English (US) |
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Pages (from-to) | 153-167.e11 |
Journal | Cancer cell |
Volume | 40 |
Issue number | 2 |
DOIs | |
State | Published - Feb 14 2022 |
Keywords
- IL-33
- ILC2
- Kras
- PDAC
- TH2
- anti-fungal therapy
- fungal mycobiome
- innate lymphoid cells
- intratumor-microbiome
- type 2 immune response
ASJC Scopus subject areas
- Oncology
- Cell Biology
- Cancer Research
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