BPTF inhibits NK cell activity and the abundance of natural cytotoxicity receptor co-ligands

// Kimberly Mayes 1 , Zeinab Elsayed 1 , Aiman Alhazmi 1 , Michael Waters 2 , Suehyb G. Alkhatib 1 , Mark Roberts 1 , Carolyn Song 1 , Kristen Peterson 1 , Vivian Chan 1 , Nikhil Ailaney 1 , Pumoli Malapati 1 , Tana Blevins 3 , Berislav Lisnic 4 , Catherine I. Dumur 3 and Joseph W. Landry 1 1 The Department of Human and Molecular Genetics, Virginia Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298, USA 2 The Department of Biochemistry, Virginia Commonwealth University, Richmond, Virginia 23298, USA 3 The Department of Pathology, Virginia Commonwealth University, Richmond, Virginia 23298, USA 4 The Center for Proteomics and Department for Histology and Embryology, University of Rijeka, Faculty of Medicine, 51000 Rijeka, Croatia Correspondence to: Joseph W. Landry, email: joseph.landry@vcuhealth.org Keywords: BPTF, chromatin remodeling, antitumor immunity, NK cell, heparanase Received: January 31, 2017 Accepted: April 26, 2017 Published: May 12, 2017 ABSTRACT Using syngeneic BALB/c mouse breast cancer models, we show that the chromatin remodeling subunit bromodomain PHD finger transcription factor (BPTF) suppresses natural killer (NK) cell antitumor activity in the tumor microenvironment (TME). In culture, BPTF suppresses direct natural cytotoxicity receptor (NCR) mediated NK cell cytolytic activity to mouse and human cancer cell lines, demonstrating conserved functions. Blocking mouse NCR1 in vivo rescues BPTF KD tumor weights, demonstrating its importance for the control of tumor growth. We discovered that BPTF occupies heparanase ( Hpse ) regulatory elements, activating its expression. Increased heparanase activity results in reduced cell surface abundance of the NCR co-ligands: heparan sulfate proteoglycans (HSPGs). Using gain and loss of function approaches we show that elevated heparanase levels suppress NK cell cytolytic activity to tumor cells in culture. These results suggest that BPTF activates heparanase expression, which in turn reduces cell surface HSPGs and NCR co-ligands, inhibiting NK cell activity. Furthermore, gene expression data from human breast cancer tumors shows that elevated BPTF expression correlates with reduced antitumor immune cell signatures, supporting conserved roles for BPTF in suppressing antitumor immunity. Conditional BPTF depletion in established mouse breast tumors enhances antitumor immunity, suggesting that inhibiting BPTF could provide a novel immunotherapy.