Abstract 2367: Tumor-infiltrating (TINKs) and tumor-associated (TANKs) natural killer cells: a new player in the inflammatory orchestration of tumor angiogenesis in colon cancer
Authors: Bruno Antonino , Bassani Barbara , Zanellato Silvia , Canali Sara , Dominioni Lorenzo , Boni Luigi , Elisa Cassinotti , David Giulia , Dallaglio Katiuscia , Mortara Lorenzo , Noonan Douglas M. , Albini Adriana 
Published: August 2015

Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide and a prevailing cause of cancer-related mortality. Several factors increase the risk of developing the tumor, including age, inflammatory bowel disease, personal and/or family history of colorectal tumors (adenoma or adenocarcinoma), and environmental factors. In spite of the extensive evidence indicating a role for inflammation in both colon cancer insurgence and progression, there is relatively little information concerning the role of inflammatory cells in CRC progression.
Natural Killer (NK) cells are effectors lymphocytes of innate immunity that can potentially control tumors by their cytotoxic activity. Several immune cells within the tumors, like macrophages, neutrophils, myeloid-derived suppressor (MSDCs) cells and dendritic cells (DCs) have been reported to acquire an altered phenotype that reflects attenuation of anti-tumor activity and enhancement of pro-tumor activities, including angiogenesis. We recently identified a peculiar NKs subset infiltrating Non Small Cell Lung Cancer (NSCLC), that we termed TINKs, described as CD56brightCD16- NKs, able to produce large amount of VEGF, PlGF and IL-8 and induce angiogenesis in vitro. We therefore extended our studies on CRC TINKs and TANKs. NK cell were isolated from blood and tissue (adjacent-normal/tumour) samples from patients with CRC then phenotipically and functionally characterized for surface antigen expression and cytokine profiling by multiparametric flow cytometry. Finally, functional studies were performed on human umbelical vein cells (HUVECs), using conditioned media (CM) derived from isolated NKs.
We found that the CD56brightCD16- NK cells predominate in both the tumors and adjacent tissues derived from colo-rectal carcinoma (CRC) samples and that are able to release substantial amounts of pro-angiogenic factors, including VEGF, PlGF and IL-8, exert low cytotoxic activities and induce migration of and capillary-like structure formation of endothelial cells in vitro. When we look at the molecular mechanisms involved in TINK and TANK angigoenic switch, we fould out that TGFβ1, an abundant cytokine within the tumor microenvironent, strongly up-regulates VEGF and PlGF release by peripheral blood NK cells from healthy age-matched donors.
Taken together, the “switched” phenotype and function of tumor infiltrating NK cells acquire a broad implications in the role of immune response against tumors, ranging from a deficient control of cancer to an altered crosstalk with other relevant players of both innate ad acquired immune response.
This places NK cells as a new player in the inflammatory orchestration of tumor angiogenesis.
Citation Format: Antonino Bruno, Barbara Bassani, Silvia Zanellato, Sara Canali, Lorenzo Dominioni, Luigi Boni, Cassinotti Elisa, Giulia David, Katiuscia Dallaglio, Lorenzo Mortara, Douglas M. Noonan, Adriana Albini. Tumor-infiltrating (TINKs) and tumor-associated (TANKs) natural killer cells: a new player in the inflammatory orchestration of tumor angiogenesis in colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2367. doi:10.1158/1538-7445.AM2015-2367