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Updated: Jun 15, 2025

Measurement of Natural Killer Cell-Mediated Cytotoxicity and Migration in the Context of Hepatic Tumor Cells
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The nuclear export protein XPO1 provides a peptide ligand for natural killer cells

Matthew D Blunt1, Hayden Fisher2,3,4, Ralf B Schittenhelm5

  • 1School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.

Science Advances
|August 23, 2024
PubMed

Insights

Exportin-1 (XPO1) is a cancer-driving protein targeted by new therapies. Researchers found XPO1 is also a tumor antigen recognized by natural killer (NK) cells, enabling personalized NK cell therapy for solid tumors.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Exportin-1 (XPO1) is a nuclear export protein overexpressed in many cancers, contributing to oncogenesis.
  • XPO1-targeting small molecules are clinically used as anticancer agents.

Purpose of the Study:

  • To identify XPO1 as a target for natural killer (NK) cells.
  • To investigate the mechanism of NK cell recognition of XPO1.
  • To explore the therapeutic potential of targeting XPO1 in cancer immunotherapy.

Main Methods:

  • Immunopeptidomics to identify tumor antigens.
  • NK cell activation assays.
  • Analysis of cancer patient data correlating XPO1 expression and NK cell infiltration with patient outcomes.

Main Results:

  • A peptide derived from XPO1 was identified as recognizable by the activating NK cell receptor KIR2DS2.
  • This XPO1-derived peptide can be endogenously processed and presented to activate NK cells via KIR2DS2.
  • High XPO1 expression, while linked to poor prognosis, showed improved outcomes in hepatocellular carcinoma with NK cell infiltration.

Conclusions:

  • XPO1 is a bona fide tumor antigen recognized by NK cells.
  • XPO1 presents a target for developing personalized NK cell-based immunotherapies for solid tumors.
  • NK cell infiltration in XPO1-expressing tumors may predict a favorable response to therapy.

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