Oral Presentation The Melbourne Immunotherapy Network Winter Symposium 2019

IL-33 signalling in gastro-intestinal cancer: foe or friend? (#17)

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

IL-33 is an IL-1 family cytokine, which regulates inflammatory responses during infections. In cancer, IL-33 can act pro or anti-tumoral depending on the tumour type and stage of disease. Here we study the mechanism of action of IL-33 signalling in gastro-intestinal cancer utilising mouse models of gastric and colorectal cancer.

For gastric cancer, Kaplan-Meyer-survival analysis showed that high expression of the IL-33 receptor, ST2, in stomach cancer patients predicts poor prognosis. In accordance, IL-33 and St2 were highly elevated in our two gastric tumour mouse models. Genetic deficiency of IL-33 signalling (ST2-/-) diminished gastric tumour growth, and was associated with a decrease in mast cells, tumour-associated macrophages (TAM) and angiogenesis. Genetic depletion or pharmacological inhibition of mast cells and TAM reduced tumour burden, again associated with decreased angiogenesis. Mechanistically, we show that tumour-produced IL-33 can activate mast cells, which in turn recruit pro-tumoral and pro-angiogenic macrophages to the tumour through release of chemo-attractants like Ccl2, Ccl3 and Ccl71.

In the colon cancer setting, ST2-deficiency lead to increased tumour burden in a mouse model of sporadic colorectal cancer. Reciprocal bone marrow chimera indicated that the radio-resistant non-hematopoietic compartment contributes to the increased tumour growth. Indeed, we found St2 expression in the mesenchymal cells, in which IL-33 stimulation induced NF-B pathway activation. Loss of IL-33 signalling in the non-haematopoietic radio-resistant compartment coincided with an increase in Treg infiltration and with a strong reduction of an IFNy gene expression signature. Furthermore, IL-33 administration reduced colon cancer allograft growth associated with tumour-infiltrating IFNy-positive T cells2.

We conclude, that tumour-derived IL-33 promotes gastric cancer growth through tumour-associated mast cells and TAM-dependent mechanisms, while IL-33 signalling within mesenchymal cells acts as a colon tumour suppressor pathway.

  1. Eissmann M, et al. IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization. Nature Communications (published online 21.6.2019)
  2. Eissmann M, et al. Interleukin 33 Signaling Restrains Sporadic Colon Cancer in an Interferon-y-Dependent Manner. Cancer Immunol Res 2018 April; 6(4):409-421.