Resistance to natural killer cell immunosurveillance confers a selective advantage to polyclonal metastasis

Area of Science:

• Cancer Biology
• Immunology
• Metastasis Research

Background:

• Polyclonal metastases originate from circulating tumor cell (CTC) clusters.
• CTC clusters show enhanced metastatic potential compared to single CTCs.
• Molecular mechanisms driving this enhanced metastasis are not well understood.

Purpose of the Study:

• To investigate the role of natural killer (NK) cells in the metastatic behavior of CTC clusters.
• To elucidate the molecular mechanisms underlying the differential resistance of polyclonal versus monoclonal CTCs to NK cell-mediated killing.
• To understand how NK cells influence metastatic clonal evolution.

Main Methods:

• Utilized breast cancer models in immunocompetent and NK cell-depleted mice.
• Quantified proportions of polyclonal lung metastasis.
• Performed transcriptional analyses of CTC clusters.
• Assessed NK cell activating ligand expression.
• Perturbed tumor cell epithelial status to evaluate NK cell sensitivity.

Main Results:

• Polyclonal metastatic seeds demonstrated increased resistance to NK cell killing.
• Immunocompetent mice showed higher proportions of polyclonal lung metastasis than NK cell-deficient mice.
• Depletion of NK cells selectively increased monoclonal, not polyclonal, metastases.
• CTC clusters exhibited elevated expression of cell-cell adhesion and epithelial genes, correlating with decreased NK cell activating ligands.
• Altering tumor cell epithelial status modulated NK ligand expression and NK cell sensitivity.

Conclusions:

• NK cells play a critical role in determining the fate of CTCs based on their epithelial and mesenchymal states.
• NK cell activity impacts metastatic clonal evolution by favoring polyclonal seeding.
• CTC clusters possess inherent resistance to NK cell-mediated suppression, contributing to their metastatic advantage.