Glycan Covalent Targeting Chimera-Based T-Cell Glycoengineering for Boosting Immunotherapy.

Area of Science:

• Immunology
• Biochemistry
• Oncology

Background:

• Chimeric antigen receptor (CAR) T-cell therapy shows efficacy in cancer immunotherapy but faces challenges in solid tumors, including antigen loss and poor infiltration.
• Modulating glycan recognition on T cells offers a novel strategy to overcome these limitations and enhance anti-tumor immunity.

Purpose of the Study:

• To develop a glycoengineering approach using glycan covalent targeting chimeras (gcTAC) to improve T-cell-mediated cancer immunotherapy.
• To enhance T-cell targeting of solid tumors and boost combined T-cell and natural killer (NK) cell therapy by manipulating glycan interactions.

Main Methods:

• Developed gcTAC using hydrazide-modified phenylboronic acid (PBA) to target T cells.
• Utilized covalent coupling between PBA's hydrazide group and oxidized galactose/N-acetylgalactosamine on T cells.
• Enabled PBA to bind sialic acids (Sia) on tumor cells, blocking Siglec-Sia interactions between tumor cells and NK cells.

Main Results:

• gcTAC enhances T-cell killing of tumor cells by targeting Sia on the tumor surface.
• Covalently bound T cells act as a blockade, disrupting tumor cell-NK cell recognition via Siglec-Sia interactions.
• This dual mechanism enhances the overall immune-killing effect in combined T-NK cell therapy.

Conclusions:

• The gcTAC approach offers a novel strategy to enhance cancer immunotherapy by intervening in T-tumor and tumor-NK cell glycan recognition.
• This method provides a potential solution to immune escape in cancer therapy, particularly for solid tumors.
• Glycoengineering T cells via gcTAC represents a promising advancement in developing more effective cancer immunotherapies.