Natural Killer Cells Control Tumor Growth by Sensing a Growth Factor

Alexander D. Barrow, Melissa A. Edeling, Vladimir Trifonov, Jingqin Luo, Piyush Goyal, Benjamin Bohl, Jennifer K. Bando, Albert H. Kim, John Walker, Mary Andahazy, Mattia Bugatti, Laura Melocchi, William Vermi, Daved H. Fremont, Sarah Cox, Marina Cella, Christian Schmedt, Marco Colonna

Research output: Contribution to journalArticle

77 Scopus citations

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.

Original languageEnglish
Pages (from-to)534-548.e19
JournalCell
Volume172
Issue number3
DOIs
StatePublished - Jan 25 2018

Keywords

  • NK cell
  • NKp44
  • PDGF-D
  • cancer
  • cell cycle
  • cytokines
  • growth factor
  • immunosurveillance
  • innate lymphoid cells

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  • Cite this

    Barrow, A. D., Edeling, M. A., Trifonov, V., Luo, J., Goyal, P., Bohl, B., Bando, J. K., Kim, A. H., Walker, J., Andahazy, M., Bugatti, M., Melocchi, L., Vermi, W., Fremont, D. H., Cox, S., Cella, M., Schmedt, C., & Colonna, M. (2018). Natural Killer Cells Control Tumor Growth by Sensing a Growth Factor. Cell, 172(3), 534-548.e19. https://doi.org/10.1016/j.cell.2017.11.037