Cytokine-mediated inflammation is a driver of gastric and colonic tumorigenesis. IL1-family cytokine Interleukin 33 (IL33) regulates inflammatory responses and antibodies targeting IL33 or its receptor ST2 are in clinical trials against various inflammatory and allergy diseases. Only recently, a role of IL33 in cancer started to emerge. Depending on the cancer stage or type IL33 can provoke either pro- or anti-tumoral responses (1). To evaluate the potential of targeting IL33 signalling to abrogate gastric and colonic cancer growth, we employ gp130Y757F/ Y757F (FF) gastric cancer mice and the 6xAOM sporadic colon cancer model as well subcutaneously engrafted MC38 colon cancer models. IL33 signalling inhibition was achieved via genetic deficiency (St2-/-), while recombinant IL33 was administered to hyper activate the IL33-signalling pathway. We found, that IL33 cytokine and ST2 receptor are overexpressed in human gastric cancers and high ST2 expression predicts poor survival for gastric cancer patients. In accordance, IL33 and ST2 are highly elevated in our FF mouse tumors. Deficiency of IL33 signalling (ST2-/-) diminishes gastric tumour growth, and is associated with a decrease in tumour-adjacent pro-tumoral mast cells and tumour-infiltrating macrophages (TAM) as well as reduced angiogenesis. Furthermore, ST2-deficiency potentiates the anti-tumor effects of oxaliplatin chemotherapy in the FF mouse model. Mechanistically, we show that tumour-produced IL33 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 Ccl7 (2). In the colon cancer setting, ST2-deficiency led to increased tumour burden in 6xAOM sporadic colorectal cancer. Reciprocal bone marrow chimera experiments indicated that the radio-resistant non-hematopoietic cell compartment contributes to the increased tumour growth. Indeed, we found St2 expression in the mesenchymal cells of the tumor microenvironment. Loss of IL33 signalling in the non-haematopoietic radio-resistant compartment coincided with a strong reduction of an IFNy gene expression signature. Importantly, IL33 cytokine administration reduced colon cancer allograft growth associated with tumour-infiltrating IFNy-positive T cells (3). Our data demonstrates the opposing roles of IL33 signalling in the growth of gastric and colonic cancers and identifies cellular mediators of these divergent tumor responses. Further studies are warranted to stratify IL33-signalling sensitive GI cancers and to verify the potential of anti-IL33/ST2 antibodies against gastric cancer and activating IL33 cytokine administration in colon cancers as novel therapy strategies. 1 Eissmann M, et al. Front Immunol 2020 Jul; 11:1389. 2 Eissmann M, et al. Nat Commun 2019 Jun; 21;10(1):2735. 3 Eissmann M, et al. Cancer Immunol Res 2018 April; 6(4):409-421.

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Citation Format: Moritz Eissmann, Christine Dijkstra, Matthias Ernst. IL33 cytokine signalling in gastrointestinal cancers - a therapy target? [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PR015.