Breast Cancer Stem Cell-Derived Tumors Escape from γδ T-cell Immunosurveillance In Vivo by Modulating γδ T-cell...

Area of Science:

• Immunology
• Oncology
• Cancer Stem Cell Biology

Background:

• Triple-negative breast cancer (TNBC) lacks targeted therapies and is driven by breast cancer stem cells (BCSCs), which contribute to metastasis and treatment resistance.
• Gamma delta (γδ) T cells are a promising immunotherapy approach due to their tumor-sensing capabilities.

Purpose of the Study:

• To investigate the efficacy of γδ T cells against TNBC stem cells (BCSCs) and understand mechanisms of immune evasion.
• To explore strategies for overcoming immunotherapy resistance in TNBC.

Main Methods:

• Patient-derived BCSCs were co-cultured with ex vivo expanded γδ T cells.
• BCSCs were orthotopically xenografted into mice and treated with γδ T cells, engineered γδ T cells, or anti-PD-1 blockade.
• Pharmacological reversion of immune escape was assessed using zoledronate or IFNα.

Main Results:

• Ex vivo expanded γδ T cells effectively killed patient-derived BCSCs.
• Orthotopically xenografted BCSCs became refractory to γδ T-cell immunotherapy due to loss of stemness and immune ligands.
• Immune escape was independent of γδ T-cell pressure and could be reversed by zoledronate or IFNα, improving survival in mice.

Conclusions:

• BCSCs develop immune evasion mechanisms that limit γδ T-cell efficacy in vivo.
• Pharmacological intervention can restore BCSC recognition by γδ T cells, suggesting novel combinatorial immunotherapy strategies for TNBC.