IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization.

2019-06-21

Eissmann, Moritz F

Dijkstra, Christine

Jarnicki, Andrew

Phesse, Toby

Brunnberg, Jamina

Poh, Ashleigh R

Etemadi, Nima

Tsantikos, Evelyn

Thiem, Stefan

Huntington, Nicholas D

Hibbs, Margaret L

Boussioutas, Alex

Grimbaldeston, Michele A

Buchert, Michael

O'Donoghue, Robert J J

Masson, Frederic

Ernst, Matthias

Journal Article

0000-0001-9568-4916

0000-0002-7137-1373

0000-0002-6399-1177

10.1038/s41467-019-10676-1

The contribution of mast cells in the microenvironment of solid malignancies remains controversial. Here we functionally assess the impact of tumor-adjacent, submucosal mast cell accumulation in murine and human intestinal-type gastric cancer. We find that genetic ablation or therapeutic inactivation of mast cells suppresses accumulation of tumor-associated macrophages, reduces tumor cell proliferation and angiogenesis, and diminishes tumor burden. Mast cells are activated by interleukin (IL)-33, an alarmin produced by the tumor epithelium in response to the inflammatory cytokine IL-11, which is required for the growth of gastric cancers in mice. Accordingly, ablation of the cognate IL-33 receptor St2 limits tumor growth, and reduces mast cell-dependent production and release of the macrophage-attracting factors Csf2, Ccl3, and Il6. Conversely, genetic or therapeutic macrophage depletion reduces tumor burden without affecting mast cell abundance. Therefore, tumor-derived IL-33 sustains a mast cell and macrophage-dependent signaling cascade that is amenable for the treatment of gastric cancer.

link

Nature Communications 2019; 10(1): 2735

Nature Communications