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Activated and expanded natural killer cells target osteosarcoma tumor initiating cells in an NKG2D-NKG2DL dependent

L Fernández1, J Valentín2, M Zalacain3

  • 1Clinical Research Department, Spanish National Cancer Research Centre CNIO, C/Melchor Fernández Almagro, 3, 28029 Madrid, Spain.

Cancer Letters
|August 16, 2015
PubMed

Insights

Natural killer (NK) cells effectively eliminate osteosarcoma (OS) cells, including treatment-resistant tumor-initiating cells (TICs). Spironolactone enhances NK cell therapy efficacy against bone cancer.

Area of Science:

  • Immunology
  • Oncology
  • Cell Biology

Background:

  • Metastatic and recurrent bone cancer, particularly osteosarcoma (OS), remains difficult to treat with current therapies.
  • Tumor-initiating cells (TICs) drive chemotherapy resistance, recurrence, and metastasis in OS.
  • Natural killer (NK) cells are crucial for innate immunity and possess anti-tumor properties.

Purpose of the Study:

  • To investigate the efficacy of activated and expanded NK (NKAE) cells in eliminating osteosarcoma (OS) cells and OS tumor-initiating cells (TICs).
  • To elucidate the molecular pathways involved in NK cell-mediated OS cell lysis.
  • To evaluate the potential of spironolactone (SPIR) in enhancing NK cell therapy for OS.

Main Methods:

  • Flow cytometry to assess NK cell receptor ligand expression on OS cells and NKAE cell targeting of OS TICs.
  • In vitro cytotoxicity assays of NKAE cells against OS cells.
  • Antibody blockade to explore NK cell-mediated lysis pathways.
  • Sphere formation assays to analyze NKAE cell targeting of OS TICs.
  • In vitro and in vivo studies of spironolactone's effect on OS cell susceptibility to NK cell lysis.

Main Results:

  • Osteosarcoma cells are susceptible to lysis by NKAE cells both in vitro and in vivo.
  • NKAE cell-mediated cytotoxicity relies on the interaction between the NKG2D receptor and NKG2D ligands (NKGKL).
  • Spironolactone enhances OS cell susceptibility to NKAE cell lysis and reduces OS TICs.
  • NKAE cells effectively target the OS TICs compartment.

Conclusions:

  • NKAE cells demonstrate significant potential in targeting and eliminating osteosarcoma cells, including TICs.
  • The NKG2D/NKG2DL pathway is critical for NK cell-mediated osteosarcoma cell killing.
  • Spironolactone can augment NK-cell based immunotherapy by increasing cancer cell susceptibility to NK cell-mediated lysis, offering a promising therapeutic strategy for osteosarcoma.
Keywords:
ImmunotherapyNKG2D–NKG2DL interactionsNatural killer cellsOsteosarcoma tumor initiating cells

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