Immunotherapy: Open Access
Open Access
ISSN: 2471-9552
ISSN: 2471-9552
Moritz Eissmann, Ernst M, Masson F, Buchert M, O Donoghue R1, Phesse T, Dijkstra C, Jarnicki A and Grimbaldeston M
Olivia Newton-John Cancer Research Institute, Australia
University of Newcastle, Australia
Centre for Cancer Biology, Australia
Posters & Accepted Abstracts: Immunother Open Acc
Innate immune cells can either promote or inhibit tumor growth. Among the different types of innate cells, the function of mast cells (MC) in gastric cancer (GC) is not well understood. Here we study the role of MC and macrophages (M�¦) in tumor initiation and maintenance in mouse models for GC. Furthermore, we explore the anti-tumorigenic potential of targeting MC/M�¦ using small molecule inhibitors. MC density was highly elevated in the sub-mucosa of gastric tumors in gp130FF-mice, in a gp130-wild type murine GC model, as well as in human GC. Genetic depletion of MC in gp130FF; cKitWsh/Wsh-mice and MC inhibition, via cromolyn administration, decreased tumor burden in gp130FF-mice. Both, MC-deficiency and pharmacological MC-inhibition were associated with decreased angiogenesis and proliferation, increased hypoxia and a reduction in tumor-associated macrophages density. Accordingly, M�¦-depletion, via clodronate treatment of gp130FF-mice led to a significant reduction of tumor burden again associated with reduced tumor angiogenesis and proliferation. Furthermore, simultaneous therapeutic MC/M�¦-targeting completely blocked gastric tumor growth in gp130FF-mice. Mechanistically, we show that IL33 is highly expressed in gp130FF tumors and that gastric MC expresses the IL33 receptor, St2. Moreover, IL33-stimulation of MC isolated from gastric tumors of gp130FF-mice increased expression and secretion of the M�¦ -attracting chemokines Ccl2, Ccl3 and Ccl7. Tumor-associated MC promote tumor growth and angiogenesis in inflammation-associated gastric cancer by recruitment of M�¦ by mechanisms likely to include IL- 33. Since individual or combined pharmacological targeting of MC/M�¦ impedes gastric tumor growth, these cells may therefore represent novel therapeutic targets for inflammation-associated GC.