Poster Presentation 31st Lorne Cancer Conference 2019

IL-33 signalling in innate immune cells drives gastric tumour growth in mice (#163)

Moritz Eissmann 1 , Christine Dijkstra 1 , Frederick Masson 1 , Matthias Ernst 1
  1. Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia

Cytokine-mediated inflammation is a driver of gastro-intestinal cancers1. Interleukin 33 (IL-33), an IL1-family cytokine, is well known for regulating inflammatory responses during infections. Only recently, a role of IL-33 in cancer development and progression starts to emerge. Depending on the cancer stage or cancer type IL-33 can provoke either pro- or anti-tumoral responses2,3. Here we study the function of IL-33 signalling, mast cells and macrophages in tumour initiation and maintenance in mouse models for gastric cancer.

We found highly increased IL-33 levels in gastric tumours of Stat3-driven gp130FF mutant mice. Stat3-Chip Seq analysis of gp130FF-tumours revealed a Stat3 binding motif on the IL-33 gene. Furthermore, IL11-stimulation (resulting in Stat3-activation) induced IL-33 gene expression in tumour organoids, confirming IL-33 as a downstream target of IL11/Stat3 signalling. IL-33 signals through its receptor St2, which we found abundantly expressed in gp130FF tumours. Kaplan-Meyer-survival analysis showed that high expression of ST2 in human intestinal-type gastric cancers predicts poor prognosis. In mice, genetic deficiency of IL-33 signalling (St2-/-) diminished gastric tumour growth, and was associated with a decrease in tumour-adjacent mast cells and tumour-associated macrophages (TAM) as well as reduced angiogenesis. Indeed, mast cell and macrophage numbers are elevated in the gp130FF-tumours compared to wild type stomachs. Genetic depletion or pharmacological inhibition of mast cells and macrophages reduced tumour burden, again associated with decreased angiogenesis. Mechanistically, we show that tumour-produced IL-33 can activate gastric gp130FF mast cells, which in turn recruit pro-tumoral and pro-angiogenic macrophages to the tumour through release of chemo-attractants like Ccl2, Ccl3 and Ccl74.

We conclude, that tumour-derived IL-33 promotes gastric cancer growth through tumour-associated mast cells and TAM-dependent mechanisms. Since individual or combined genetic and pharmacological targeting of IL-33/ST2, mast cells and macrophages impedes gastric tumour growth, either the IL-33/St2 signalling node or both cell types may therefore represent novel therapeutic targets against inflammation-associated gastric cancer.

  1. Ernst M, Thiem S, Nguyen PM, Eissmann M and Putoczki TL (2014). Epithelial gp130/Stat3 functions: an intestinal signaling node in health and disease. Semin Immunol 26(1):29-37
  2. Wasmer MH and Krebs P (2017). The Role of IL-33-Dependent Inflammation in the Tumor Microenvironement. Front Immunol 7:682.
  3. Eissmann M, Dijkstra C, Wouters MA, Baloyan D, Mouradov D et al. (2018). Interleukin 33 Signaling Restrains Sporadic Colon Cancer in an Interferon-y-Dependent Manner. Cancer Immunol Res 6(4):409-421.
  4. Eissmann M, Jarnicki A, Dijkstra C, Phesse T, Brunnberg J et al. IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization. Nat Commun (provisionally accepted)