Barrow, Alexander/D, Edeling, Melissa/A, Trifonov, Vladimir, Luo, Jingqin, Goyal, Piyush, Bohl, Benjamin, Bando, Jennifer, Kim, Albert, Andahazy, Mary, Melocchi, Laura, Bugatti, Mattia, Vermi, Wiliam, Fremont, Daved, Cox, Sarah, Cella, Marina, Schmedt, Christian and Colonna, Marco (2018) Natural Killer Cells Control Tumor Growth by Sensing a Growth Factor. Cell, 172 (3). 534-548.e19. ISSN 10974172

Abstract

Many tumors produce platelet-derived growth factor (PDGF)-DD, which promotes cellular proliferation, epithelial-mesenchymal transition, stromal reaction, and angiogenesis through autocrine and paracrine PDGFRβ signaling. By screening a secretome library, we found that the human immunoreceptor NKp44, encoded by NCR2 and expressed on natural killer (NK) cells and innate lymphoid cells, recognizes PDGF-DD. PDGF-DD engagement of NKp44 triggered NK cell secretion of interferon gamma (IFN)-γ and tumor necrosis factor alpha (TNF-α) that induced tumor cell growth arrest. A distinctive transcriptional signature of PDGF-DD-induced cytokines and the downregulation of tumor cell-cycle genes correlated with NCR2 expression and greater survival in glioblastoma. NKp44 expression in mouse NK cells controlled the dissemination of tumors expressing PDGF-DD more effectively than control mice, an effect enhanced by blockade of the inhibitory receptor CD96 or CpG-oligonucleotide treatment. Thus, while cancer cell production of PDGF-DD supports tumor growth and stromal reaction, it concomitantly activates innate immune responses to tumor expansion. The growth factor PDGF-DD, expressed by multiple types of tumors, is a stimulatory ligand for human NK cell receptor NKp44.

Item Type:	Article
Keywords:	cancer cell cycle cytokines growth factor immunosurveillance innate lymphoid cells NK cell NKp44 PDGF-D
Date Deposited:	20 Mar 2018 00:45
Last Modified:	25 Jan 2019 00:45
URI:	https://oak.novartis.com/id/eprint/34504