Stroma-derived ANGPTL2 establishes an anti-tumor microenvironment during intestinal tumorigenesis

Previous studies show that tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) functions as a tumor promoter in some cancer contexts. However, we recently reported that host ANGPTL2 also shows tumor suppressive activity by enhancing dendritic cell-mediated CD8⁺ T cell anti-tumor immune responses in mouse kidney cancer and murine syngeneic models. However, mechanisms underlying ANGPTL2-mediated tumor suppression are complex and not well known. Here, we investigated ANGPTL2 tumor suppressive function in chemically-induced intestinal tumorigenesis. ANGPTL2 deficiency enhanced intestinal tumor growth in an experimental mouse colitis-associated colon cancer (CAC) model. Angptl2-deficient mice also showed a decrease not only in CD8⁺ T cell responses but in CD4⁺ T cell responses during intestinal tumorigenesis. Furthermore, we show that stroma-derived ANGPTL2 can activate the myeloid immune response. Notably, ANGPTL2 drove generation of immunostimulatory macrophages via the NF-κB pathway, accelerating CD4⁺ T helper 1 (Th1) cell activation. These findings overall provide novel insight into the complex mechanisms underlying ANGPTL2 anti-tumor function in cancer pathology.