Margaret L. Hibbs, Michael Buchert, Matthias Ernst, Frederick Masson, Alex Boussioutas, Nima Etemadi, Moritz F. Eissmann, Jamina Brunnberg, Ashleigh R Poh, Toby J. Phesse, Robert J.J. O'Donoghue, Evelyn Tsantikos, Stefan Thiem, Andrew G. Jarnicki, Nicholas D. Huntington, Christine D. Dijkstra, Michele A. Grimbaldeston, Cancer and Inflammation Laboratory [Heidelberg, VIC, Australia] (School of Cancer Medicine), Olivia Newton-John Cancer Research Institute [Heidelberg, VIC, Australia]-La Trobe University [Melbourne], Department of Immunology and Pathology [Melbourne, VIC, Australia], Monash University [Melbourne], Molecular Immunology Division melbourne [Melbourne, VIC, Australia], The Walter and Eliza Hall Institute of Medical Research (WEHI), Department of Medical Biology [Melbourne, VIC, Australia], University of Melbourne, Department of Medicine [Melbourne, VIC, Australia], Centre for Cancer Biology [Adelaide, SA, Australia], University of South Australia [Adelaide]-SA Pathology [Adelaide, SA, Australia], This work was supported through the Victorian State Government Operational Infrastructure Support, the Nation Health and Medical Research Council (NHMRC) of Australia grants 1092788, 1067244, 1069024 and Cancer Council Victoria’s Grant-in-Aid 1160708. M.E. is a NHMRC Principal Research Fellow and also received funding from Ludwig Cancer Research., 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 JJ, Masson, Frederick, and Ernst, Matthias
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., Mast cells within the tumor microenvironment have controversial roles. Here, the authors show, using genetic mouse models, that in gastric cancer, mast cells at the periphery of the tumors are activated via cancer cell produced-IL33 and promote tumorigenesis by recruiting macrophages within the tumors.