Angiogenin and the MMP9-TIMP2 axis are up-regulated in proangiogenic, decidual NK-like cells from patients with colorectal cancer

NK cells are effector lymphocytes involved in tumor immunosurveillance; however, in patients with solidmalignancies,NKcells have compromised functions.Wehave previously reported that lung tumor-associated NKcells (TANKs; peripheralblood) andtumor-infiltratingNKcells (TINK_s) showproangiogenic,decidualNK-like (dNK) phenotype. In this study, we functionally andmolecularly investigated TINK_s and TANK_s fromblood and tissue samples of patients with colorectal cancer (CRC), a neoplasmin which inflammation and angiogenesis have clinical relevance, and compared them to NK cells from controls and patients with nononcologic inflammatory bowel disease. CRC TINK_s/TANK_s showed decreased expression for the activatory marker NKG2D, impaired degranulation activity, a decidual-likeNKpolarization toward the CD5^6brightCD16^dim/-2CD9⁺CD49⁺ subset. TINKs and TANKs secreted cytokines with proangiogenic activities, and induce endothelial cell proliferation, migration, adhesion, and the formation of capillary-like structures in vitro. dNK cells release specific proangiogenic factors; amongwhich, angiogenin and invasion-associated enzymes related to theMMP9-TIMP1/2 axis.Here,we describe, for the first time, to our knowledge, the expression of angiogenin,MMP2/9, and TIMP by TANK_s in patients with CRC. This phenotype could be relevant to the invasive capabilities and proangiogenic functions of CRC-NK cells and become a novel biomarker. STAT3/STAT5 activation was observed in CRC-TANK_s, and treatment with pimozide, a STAT5 inhibitor, reduced endothelial cell capability to form capillary-like networks, inhibiting VEGF and angiogenin production without affecting the levels of TIMP1, TIMP2, and MMP9, indicating that STAT5 is involved in cytokine modulation but not invasion-associated molecules. Combination of Stat5 orMMP inhibitors with immunotherapy could help repolarizeCRCTINK_s and TANK_s to anti-tumor antimetastatic ones.