Barrow, Alexander/D and Edeling, Melissa/A and Trifonov, Vladimir and Luo, Jingqin and Goyal, Piyush and Bohl, Benjamin and Bando, Jennifer and Kim, Albert and Andahazy, Mary and Melocchi, Laura and Bugatti, Mattia and Vermi, Wiliam and Fremont, Daved and Cox, Sarah and Cella, Marina and 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