CD56-mediated NK cell activation: a novel innate immune axis in bladder cancer 2070

Description Natural Killer (NK) cells target cancer cells independently of antigen specificity, overcoming tumor escape from immunity. We previously showed that NK cells are one of the predominant tumor-infiltrating lymphocytes in bladder cancer (BCa) and correlate with improved patient survival. However, that link was observed with only CD56bright NK cells while the CD56dim subset exhibited reduced cytotoxicity and higher accumulation in advanced BCa stages. Importantly, the presence of CD56bright NK cells correlates with improved patient survival, independent of tumor stage. Significant reductions in NK cell cytotoxicity and activation against BCa following CD56 deletion were observed through flow cytometry and cytotoxicity assays. Further, migration assays and atomic force microscopy showed CD56 deletion impaired NK cell migration and adhesion to bladder tumor cells, reducing NK cell-mediated apoptosis of BCa cells. Prolonged exposure to bladder tumors led to CD56 loss in NK cells, indicating tumor-induced NK cell dysfunction via CD56 reduction. Furthermore, confocal microscopy revealed that CD56 colocalizes with phosphorylated Pyk2, mediating downstream cytotoxic effects. Lastly, we showed that CD56 is also expressed by BCa cells and may be a predictive biomarker for NK cell-based immunotherapy, with its shedding indicating a mechanism for NK cell evasion, identifying a novel innate-immune axis in BCa. Funding Sources Supported by the Mays Family Cancer Center at University of Texas Health San Antonio Roger L. And Laura D. Zeller Charitable Foundation Chair in Urologic Cancer Glenda and Gary Woods Distinguished Chair in GU Oncology Max & Minnie Tomerlin Voelcker Fund Bladder Cancer Advocacy Network (BCAN)