MP92-04 PROTUMOR CONVERSION OF NATURAL KILLER CELLS BY TRANSFORMING GROWTH FACTOR-β AND HYPOXIA IN RENAL CELL CARCINOMA

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology III1 Apr 2016MP92-04 PROTUMOR CONVERSION OF NATURAL KILLER CELLS BY TRANSFORMING GROWTH FACTOR-β AND HYPOXIA IN RENAL CELL CARCINOMA Yue Guan, Christopher B. Chambers, Max Nutt, Britnie James, Kathy Robinson, Shaheen Alanee, MD, MPH, MBA Thomas Griffith, Donald Torry, and Andrew Wilber Yue GuanYue Guan More articles by this author , Christopher B. ChambersChristopher B. Chambers More articles by this author , Max NuttMax Nutt More articles by this author , Britnie JamesBritnie James More articles by this author , Kathy RobinsonKathy Robinson More articles by this author , Shaheen AlaneeShaheen Alanee More articles by this author , Thomas GriffithThomas Griffith More articles by this author , Donald TorryDonald Torry More articles by this author , and Andrew WilberAndrew Wilber More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2637AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES NK cells with non-classical phenotypes (CD56+CD16dim/neg; termed decidua NK or dNK cells) accumulate at the maternal-fetal interface during implantation. These dNK cells are poorly cytotoxic and proangiogenic. We investigated whether an analogous NK cell phenotype accumulate in RCC tumors potentiated by tumor-derived TGFβ and hypoxia. METHODS NK cells from peripheral blood (pNK) and resected tumor tissue (TiNK) of RCC patients were compared to pNK from healthy, tumor-free donors. pNK cells were cultured in the absence or presence of TGFß and exposed to 21% or 1% oxygen to assess conversion by monitoring expression of surface markers and angiogenic genes as well as ability to directly kill target cells. An orthotopic mouse model of RCC was also used, where the murine renal adenocarcinoma cell line, Renca, was implanted directly into the kidneys of Balb/c mice. RESULTS pNK cells of healthy donors were CD56+CD16+ (94±1%) and cytotoxic, but acquired characteristics of dNK cells (reduced cytotoxicity and augmented vascular endothelial growth factor (VEGF) expression) when exposed to TGFß or 1% O2. Addition of TGFß to NK cells maintained in 1% O2 further suppressed cytotoxic function and induced expression of urokinase plasminogen activator (uPA) and its inhibitor PAI-1, two factors with known roles in tumor progression. pNK cells of RCC patients were phenotypical similar to healthy donors (89±2%, CD56+CD16+), but lacked full cytotoxic ability which we attributed to 3-fold higher levels of TGFß in patient serum. RCC TiNK cells were significantly enriched for dNK-like CD56+CD16dim/neg cells (47±-12%) had limited cytotoxic capacity and increased VEGF and uPA expression. Analogous alterations in TiNK cells were observed using an orthotopic mouse model of RCC. CONCLUSIONS These studies support a role for TGFß and hypoxia in conversion of pNK cells to a dNK-like phenotype in RCC tumors. While these characteristics are conceivably beneficial for placentation, they may be exploited to support RCC growth and metastasis. Thus, efforts designed to neutralize the effects of TGFß may be an important goal of future immunotherapies. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1162-e1163 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Yue Guan More articles by this author Christopher B. Chambers More articles by this author Max Nutt More articles by this author Britnie James More articles by this author Kathy Robinson More articles by this author Shaheen Alanee More articles by this author Thomas Griffith More articles by this author Donald Torry More articles by this author Andrew Wilber More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...