Enhanced CCR2 expression by ACKR2-deficient NK cells increases tumoricidal cell therapy efficacy

Area of Science:

• Immunology
• Cancer Biology
• Cell Therapy

Background:

• Chemokines guide leukocytes to specific sites, impacting cell therapy homing.
• Atypical chemokine receptor 2 (ACKR2)-deficient mice show reduced metastasis, linked to enhanced natural killer (NK) cell homing.
• Enhanced NK cell homing in ACKR2-/- mice was previously attributed to increased CCR2 expression.

Purpose of the Study:

• To investigate the direct role of ACKR2 in metastasis suppression.
• To determine the cause of enhanced CCR2 expression on NK cells in ACKR2-/- mice.
• To evaluate the therapeutic potential of CCR2+ NK cells in anti-metastatic strategies.

Main Methods:

• Utilized ACKR2-deficient (ACKR2-/-) mouse models.
• Analyzed NK cell populations and CCR2 expression.
• Investigated the genetic origins of enhanced NK cell CCR2 expression.
• Assessed the anti-metastatic capabilities of selected CCR2+ NK cells.

Main Results:

• The metastatic-suppression phenotype in ACKR2-/- mice is not a direct effect of ACKR2 absence.
• Enhanced NK cell CCR2 expression resulted from passenger mutations during ACKR2-/- mouse strain creation.
• Selection of CCR2+ NK cells enriched a population with superior anti-metastatic capabilities.
• Tumors commonly express CCR2 ligands, indicating a targetable pathway.

Conclusions:

• ACKR2 deficiency does not directly confer anti-metastatic properties.
• Passenger mutations, not ACKR2 absence, drive enhanced NK cell CCR2 expression and anti-metastatic function.
• CCR2+ NK cells possess significant anti-metastatic potential.
• Targeting CCR2+ NK cells represents a promising strategy for cell-based tumoricidal therapy.