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TL1A drives ILC-mediated granulopoiesis and colitis associated cancer

ABSTRACT: The incidence of colorectal cancer (CRC) is increased in patients with ulcerative colitis (UC) and accounts for up to 15% annual mortality in patients with inflammatory bowel disease (IBD). Variants in TNFSF15, the gene that encodes TL1A, are associated with more aggressive IBD and advanced CRC. Here, we show that TL1A signaling is required for colitis-associated tumorigenesis and sufficient to promote CRC in mouse models. TL1A signaling in group 3 innate lymphoid cells (ILC3) promotes GM-CSF dependent activation of colonic neutrophils and colitis-associated tumors in mouse models. TL1A-mediated, ILC3-dependent tumor-associated neutrophil (TAN) signatures were evident in mouse models and reduced in subjects with UC treated with anti-TL1A therapy. Furthermore, TL1A promoted ILC-dependent emergency granulopoiesis, which is similarly evident in IBD subjects with TNFSF15 risk variants. These results reveal a new mechanism by which TL1A signaling in tissue resident ILCs shape TANs and emergency granulopoiesis with the potential to guide emerging anti-TL1A therapies for IBD.

ORGANISM(S): Mus musculus

PROVIDER: GSE248113 | GEO | 2025/11/23

REPOSITORIES: GEO

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