Mutant KRAS promotes type 2 immunity through upregulation of IL33 in pancreatic ductal adenocarcinoma (PDAC).

  • Major Finding: Mutant KRAS promotes type 2 immunity through upregulation of IL33 in PDAC.

  • Concept: IL33 secretion is enhanced by the intratumoral mycobiome and leads to TH2 and ILC2 infiltration.

  • Impact: The mechanistic insight provided suggests the IL33/ TH2/ILC2 axis as a potential target in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a suppressive immune profile with infiltration of immune suppressor cells, such as CD4+ TH2 cells, which can fuel PDAC progression. However, it remains unknown how TH2 and other type 2 immune cells are trafficked to the tumor microenvironment (TME). Therefore, Alam and colleagues investigated the mechanisms that drive recruitment and expansion of TH2 cells in the PDAC TME. Initial experiments revealed increased recruitment of type 2 immune cells to the PDAC TME, including TH2 cells as well as innate lymphoid cells 2 (ILC2). As type 2 immunocyte infiltration and mutations in KRAS occur early in PDAC development, KrasG12D-regulated transcripts were investigated and indicated a 30-fold enrichment of Il33 transcripts upon Kras mutation that was also confirmed at the protein level. Additionally, treatment with a MEK inhibitor, but not an inhibitor of PI3K, reduced IL33 expression, suggesting induction of IL33 occurs via the KRAS–MEK–ERK signaling pathway. Genetic depletion of IL33 from cancer cells showed no effect on in vitro cancer cell growth, but in vivo tumor burden was reduced and survival was extended in a syngeneic orthotopic PDAC model. Furthermore, TH2 and ILC2 infiltration was decreased upon IL33 depletion. Expression of IL33 was found to be predominantly nuclear in precursor lesions, which becomes more widespread in advanced adenocarcinoma, but cells in culture showed only nuclear staining, suggesting environmental stimuli may also regulate IL33 secretion. Previous studies have demonstrated that IL33 secretion can be regulated by the presence of fungus, thus investigation into this phenomenon in PDAC mouse models revealed the presence of a mycobiome at high abundance in tumors as well as that treatment with an antifungal decreased tumor-infiltrating ILC2 and TH2 cells, reduced tumor burden, and increased survival. This study reports the role of IL33 and its effect on the type 2 immune response in PDAC progression and suggests the targeting of this axis as a potential treatment target in this disease.

Alam A, Levanduski E, Denz P, Villavicencio HS, Bhatta M, Alhorebi L, et al. Fungal mycobiome drives IL-33 secretion and type 2 immunity in pancreatic cancer. Cancer Cell 2022;40:153–67.e11.

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