Advertisement

Natural killer cells control metastasis via structural editing of primary tumors in mice

  • Batya Isaacson
  • Ofer MandelboimEmail author
Focussed Research Review

Abstract

Natural killer (NK) cells are innate immune lymphocytes which express an array of activating and inhibitory receptors. These receptors bind a large spectrum of ligands, which are expressed on stressed, malignantly transformed or virally infected cells, as well as on bacterial, fungal, and parasitic pathogens. The decision on whether or not to kill the target is based on the integration of activating and inhibitory signals sent downstream from NK cell receptors. One of the most prominent NK cell activating receptor families is the family of natural cytotoxicity receptors (NCRs) which includes NKp30, NKp44, and NKp46. NKp46 is the only NCR to have a fully functional mouse orthologue denoted Ncr1. Despite a large body of evidence highlighting its importance in the clearance of both solid and liquid tumors, the membrane-bound tumor ligand for NKp46 and its mouse orthologue Ncr1 is still unknown. Here we review the discovery of a novel role for NKp46/Ncr1, not only in tumor clearance but also in prevention of metastasis by structural editing of primary tumors.

Keywords

NK cells NKp46 Ncr1 IFNγ FN1 TIMO2018 

Abbreviations

FN1

Fibronectin1

IFNγ

Interferon gamma

KO

Knock out

MHC

Major histocompatibility complex

NCR

Natural cytotoxicity receptor

NK

Natural killer

RCM

Reflectance confocal microscopy

TNFα

Tumor necrosis factor alpha

Notes

Author contributions

Batya Isaacson wrote the first draft and Ofer Mandelboim edited the manuscript. Both authors revised the manuscript and approved the final version of this paper.

Funding

This work was supported by the Israel Science Foundation (Moked grant and Israel-China grant), the German-Israeli Foundation for Scientific Research and Development (GIF), the Israel Cancer Research Fund (ICRF) professorship grant, and the Ministry of Science and Technology grant (all to Ofer Mandelboim.).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interests.

References

  1. 1.
    Kiessling R, Klein E, Pross H, Wigzell H (1975) “Natural” killer cells in the mouse II cytotoxic cells with specificity for mouse Moloney leukemia cells characteristics of the killer cell. Eur J Immunol.  https://doi.org/10.1002/eji.1830050209 CrossRefPubMedGoogle Scholar
  2. 2.
    Koch J, Steinle A, Watzl C, Mandelboim O (2013) Activating natural cytotoxicity receptors of natural killer cells in cancer and infection. Trends Immunol 34:182–191.  https://doi.org/10.1016/j.it.2013.01.003 CrossRefPubMedGoogle Scholar
  3. 3.
    Toledano T, Vitenshtein A, Stern-Ginossar N et al (2018) Decay of the stress-induced ligand MICA is controlled by the expression of an alternative 3′ untranslated region. J Immunol.  https://doi.org/10.4049/jimmunol.1700968 CrossRefPubMedGoogle Scholar
  4. 4.
    Elias S, Yamin R, Golomb L et al (2014) Immune evasion by oncogenic proteins of acute myeloid leukemia. Blood.  https://doi.org/10.1182/blood-2013-09-526590 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Tsukerman P, Stern-Ginossar N, Yamin R et al (2014) Expansion of CD16 positive and negative human NK cells in response to tumor stimulation. Eur J Immunol.  https://doi.org/10.1002/eji.201344170 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Dassa L, Seidel E, Oiknine-Djian E et al (2018) The human cytomegalovirus protein UL148A downregulates the NK cell-activating ligand MICA to avoid NK cell attack. J Virol.  https://doi.org/10.1128/JVI.00162-18 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Seidel E, Le VTK, Bar-On Y et al (2015) Dynamic co-evolution of host and pathogen: HCMV downregulates the prevalent allele MICA*008 to escape elimination by NK cells. Cell Rep 10:968–982.  https://doi.org/10.1016/j.celrep.2015.01.029 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Chowdhury D, Lieberman J (2008) Death by a thousand cuts: granzyme pathways of programmed cell death. Annu Rev Immunol.  https://doi.org/10.1146/annurev.immunol.26.021607.090404 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Mandelboim O, Lieberman N, Lev M et al (2001) Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells. Nature 409:1055–1060.  https://doi.org/10.1038/35059110 CrossRefPubMedGoogle Scholar
  10. 10.
    Bar-On Y, Charpak-Amikam Y, Glasner A et al (2017) NKp46 recognizes the sigma1 protein of reovirus: implications for reovirus-based cancer therapy. J Virol.  https://doi.org/10.1128/JVI.01045-17 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Vitenshtein A, Charpak-Amikam Y, Yamin R et al (2016) NK cell recognition of Candida glabrata through binding of NKp46 and NCR11 to fungal ligands Epa1, Epa6, and Epa7. Cell Host Microbe 20:527–534.  https://doi.org/10.1016/j.chom.2016.09.008 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Elboim M, Gazit R, Gur C et al (2010) Tumor immunoediting by NKp46. J Immunol.  https://doi.org/10.4049/jimmunol.0901644 CrossRefPubMedGoogle Scholar
  13. 13.
    Lakshmikanth T, Burke S, Ali TH et al (2009) NCRs and DNAM-1 mediate NK cell recognition and lysis of human and mouse melanoma cell lines in vitro and in vivo. J Clin Invest.  https://doi.org/10.1172/JCI36022 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Morvan M, Lanier L (2015) NK cells and cancer: you can teach innate cells new tricks. Nat Rev Cancer 16:7–19.  https://doi.org/10.1038/nrc.2015.5 CrossRefGoogle Scholar
  15. 15.
    Gazit R, Gruda R, Elboim M et al (2006) Lethal influenza infection in the absence of the natural killer cell receptor gene Ncr1. Nat Immunol 7:517–523.  https://doi.org/10.1038/ni1322 CrossRefPubMedGoogle Scholar
  16. 16.
    Halfteck GG, Elboim M, Gur C et al (2009) Enhanced in vivo growth of lymphoma tumors in the absence of the NK-activating receptor NKp46/NCR16. J Immunol.  https://doi.org/10.4049/jimmunol.0801878 CrossRefPubMedGoogle Scholar
  17. 17.
    Glasner A, Ghadially H, Gur C et al (2012) Recognition and prevention of tumor metastasis by the NK receptor NKp46/NCR17. J Immunol.  https://doi.org/10.4049/jimmunol.1102461 CrossRefPubMedGoogle Scholar
  18. 18.
    Glasner A, Levi A, Enk J et al (2018) NKp46 receptor-mediated interferon-g production by natural killer cells increases fibronectin 1 to alter tumor architecture and control metastasis. Immunity 48:1–13.  https://doi.org/10.1016/j.immuni.2017.12.007 CrossRefGoogle Scholar
  19. 19.
    Pellacani G, Guitera P, Longo C et al (2007) The impact of in vivo reflectance confocal microscopy for the diagnostic accuracy of melanoma and equivocal melanocytic lesions. J Invest Dermatol.  https://doi.org/10.1038/sj.jid.5700993 CrossRefPubMedGoogle Scholar
  20. 20.
    Giancotti FG, Ruoslahti E (1999) Transduction—{Integrin} signaling. Science (80-).  https://doi.org/10.1126/science.285.5430.1028 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, The Hebrew University Medical SchoolIMRICJerusalemIsrael

Personalised recommendations