Modulation of NKG2D, NKp46, and Ly49C/I facilitates natural killer cell-mediated control of lung cancer

Proc Natl Acad Sci U S A. 2018 Nov 13;115(46):11808-11813. doi: 10.1073/pnas.1804931115. Epub 2018 Oct 31.


Natural killer (NK) cells play a critical role in controlling malignancies. Susceptibility or resistance to lung cancer, for example, specifically depends on NK cell function. Nevertheless, intrinsic factors that control NK cell-mediated clearance of lung cancer are unknown. Here we report that NK cells exposed to exogenous major histocompatibility class I (MHCI) provide a significant immunologic barrier to the growth and progression of malignancy. Clearance of lung cancer is facilitated by up-regulation of NKG2D, NKp46, and other activating receptors upon exposure to environmental MHCI. Surface expression of the inhibitory receptor Ly49C/I, on the other hand, is down-regulated upon exposure to tumor-bearing tissue. We thus demonstrate that NK cells exhibit dynamic plasticity in surface expression of both activating and inhibitory receptors based on the environmental context. Our data suggest that altering the activation state of NK cells may contribute to immunologic control of lung and possibly other cancers.

Keywords: NK cells; immunosurveillance; immunotherapy; lung cancer; tumor immunology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Ly / immunology*
  • Cytotoxicity, Immunologic
  • Down-Regulation
  • Histocompatibility Antigens Class I / metabolism
  • Killer Cells, Natural / immunology*
  • Lung Neoplasms / immunology*
  • Lung Neoplasms / metabolism
  • Mice
  • Mice, Inbred C57BL
  • NK Cell Lectin-Like Receptor Subfamily A / immunology*
  • NK Cell Lectin-Like Receptor Subfamily K / immunology*
  • Natural Cytotoxicity Triggering Receptor 1 / immunology*
  • Receptors, Immunologic / immunology*
  • Receptors, Natural Killer Cell / metabolism*
  • Up-Regulation


  • Antigens, Ly
  • Histocompatibility Antigens Class I
  • Klra3 protein, mouse
  • Klrk1 protein, mouse
  • Ly49I antigen
  • NK Cell Lectin-Like Receptor Subfamily A
  • NK Cell Lectin-Like Receptor Subfamily K
  • Natural Cytotoxicity Triggering Receptor 1
  • Ncr1 protein, mouse
  • Receptors, Immunologic
  • Receptors, Natural Killer Cell