Chemical engineering of γδ T cells with cancer cell-targeting antibodies for enhanced tumor immunotherapy

Area of Science:

• Immunology
• Biotechnology
• Cancer Therapy

Background:

• Gamma delta (γδ) T cells show therapeutic potential but have limited tumor targeting.
• Current strategies face challenges in enhancing γδ T cell efficacy against tumors.

Purpose of the Study:

• To develop antibody-γδ T cell conjugates for improved tumor targeting and adoptive cell therapy.
• To engineer γδ T cells using metabolic glycan labeling and click chemistry for enhanced cancer treatment.

Main Methods:

• Utilized metabolic glycan labeling to anchor antibodies onto γδ T cells via sialic acids.
• Employed click chemistry to conjugate a programmed death-ligand 1 (PD-L1)-specific nanobody (αPD-L1) onto γδ T cells.
• Evaluated the efficacy of αPD-L1-γδ T cells against various cancer models, including cell lines, primary cells, and xenografts.

Main Results:

• αPD-L1-γδ T cells demonstrated enhanced cytotoxicity against PD-L1-positive cancer cells and tumors.
• Engineered γδ T cells induced cancer cell pyroptosis and remodeled the tumor microenvironment.
• Observed recruitment and activation of CD8+ T cells via the CCR5/CCL5 axis, indicating an immune-active tumor microenvironment.

Conclusions:

• Antibody conjugation via metabolic glycan labeling offers a versatile strategy for engineering γδ T cells.
• This approach significantly improves γδ T cell-mediated tumor targeting and therapeutic efficacy.
• The engineered γδ T cells hold promise for advancing adoptive cell therapy in cancer treatment.