Innate lymphoid cells activated by the cytokine TL1A link colitis to emergency granulopoiesis and the recruitment of tumor-promoting neutrophils.

Inflammatory bowel disease (IBD) increases the risk of colorectal cancer (CRC). Genetic variants in TNFSF15, encoding tumor necrosis factor (TNF)-like cytokine 1A (TL1A), associate with severe IBD and advanced CRC. Here, we investigated how TL1A signaling promotes colitis-associated tumorigenesis. Deletion of the TL1A receptor in tissue-resident type 3 innate lymphoid cells (ILC3s) reduced colitis-associated tumorigenesis. TL1A signaling promoted neutrophil recruitment to the colon, which was required for tumor development. TL1A-stimulated ILC3s activated neutrophils, inducing a tumor-associated neutrophil (TAN)-like gene signature, and transfer of these neutrophils was sufficient to promote tumor growth. A similar TAN-like gene signature was enriched in human colitis-associated dysplasia but reduced following TL1A blockade in ulcerative colitis patients. Mechanistically, TL1A and colitis triggered emergency granulopoiesis, expanding granulocyte-monocyte progenitors and neutrophils in a manner dependent on ILC3-derived granulocyte-macrophage colony-stimulating factor (GM-CSF). Thus, a TL1A-ILC3-GM-CSF axis links colitis with emergency granulopoiesis and may serve as a therapeutic target to reduce colitis-associated CRC.