Tumor-infiltrating (TINKs) and tumor-associated (TANKs) natural killer cells: a new player in the inflammatory orchestration of tumor angiogenesis in colon cancer

Natural Killer (NK) cells are lymphocytes of innate immunity that can potentially control tumors by their cytotoxic activity. The NK cells of patients with NSCLC, both tumor infiltrating (TINKs) and tumor associated (TANKs, from peripheral blood), are poorly cytotoxic, CD56brightCD16-, producing substantial levels of VEGF, PlGF, IL-8 and induce angiogenesis in vitro. In the present study we extended our analysis on colorectal cancer (CRC) TINKs and TANKs. NK cell were isolated from blood and tissue (adjacent-normal and tumor tissues) from patients with CRC then phenotypically and functionally characterized for surface antigen expression and cytokine profiling by multiparametric flow cytometry. Functional angiogenesis assays were performed on human umbilical vein cells, using conditioned media derived from isolated NK cells. We found that the CD56brightCD16- NK cells predominate in both the tumors and adjacent tissues derived from CRC samples. The CRC TINKs are poorly cytotoxic and express markers of decidual NK cells (CD9 and CD49a). TINKs produce pro-angiogenic factors, including VEGF, PlGF and IL-8, associated with induction of migration and capillary-like structure formation of endothelial cells in vitro. TANKS also produced VEGF. The “switched” phenotype and function of tumor infiltrating NK cells acquire a broad implications in the role of immune response against tumors and this places NK cells as a new playe r in the inflammatory promotion of tumor angiogenesis.