Abstract 121: Angiogenin and the mmp9-timp2 axis are strongly upregulated in pro-angigoenic dnk-like cells isolated from colorectal cancer patients

Abstract

Abstract Natural Killer (NK) cells are effector lymphocytes involved in tumor immunosurveillance. In solid malignancies, tumor associated (TANK; peripheral blood) and tumor infiltrating (TINK) NK cells have compromised functions. We functionally and molecularly characterize TINK and TANKs from blood and tissue samples of colorectal cancer (CRC) patients, a tumor type where inflammation and angiogenesis have clinical relevance, compared to NK isolated from control and non-oncologic inflammatory bowel disease patients. NK subset distribution and cytokine profiling were performed by multicolor flow cytometry, using peripheral blood and tissue samples from CRC patients, for surface antigen and cytokine profiling characterization. Conditioned media (CM) from FACS-sorted NKs were used either for secretomic profiling using antibody membrane arrays or in functional in vitro angiogenesis assays. CRC TINKs/TANKs showed decreased activation marker NKG2D, impaired degranulation activity, a decidual-like NK polarization toward the CD56brightCD16dim/- CD9+CD49+ subset. TINKs and TANKs supernatants induced endothelial cell proliferation, migration, adhesion and formation of capillary-like structures in vitro. It has been reported that dNK release proangiogenic factors and metastasis-associated (MMP-9, TIMP1-2) proteins. We describe for the first time the expression of angiogenin and MMP2, MMP9, TIMP1 and TIMP2 by CRC derived NK cells. This could be a phenotype relevant to their invasive capabilities and pro-angiogenic function. STAT-3/STAT-5 activation was observed in TANKs, and inhibition of the STAT5 pathway by pimozide, an antipsychotic drug, reduced proangiogenic factor VEGF and angiogenin production and capillary-like structure formation, but did not affect the levels of TIMP-1, TIMP-2 and MMP-9. Citation Format: Antonino Bruno, Giuseppe Pelosi, Luigi Boni, Lorenzo Dominioni, Lorenzo Mortara, Douglas Noonan, Adriana Albini. Angiogenin and the mmp9-timp2 axis are strongly upregulated in pro-angigoenic dnk-like cells isolated from colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 121.