image: Using the fast metabolic glycan labeling (fMGL) technique, AMS-ManNAz-P was incorporated into the terminal sialic acids of various cell-surface glycans on γδ T cells. The modified γδ T cells were then conjugated with αPD-L1 via copper-free click chemistry to produce the αPD-L1–γδ T cell conjugates. The targeting antibody αPD-L1 on the conjugates first facilitates γδ T cell binding to PD-L1–expressing cancer cells, which subsequently triggers interactions between TCR γδ and BTN3A1/2A1, co-stimulatory receptors and ligands, as well as death ligands and receptors. This activation leads γδ T cells to release cytotoxic cytokines. In cancer cells, caspase-3 is activated and cleaves GSDME, initiating pyroptosis. Within the tumor microenvironment (TME), CCL5 was released from the culture of αPD-L1–γδ T cells and tumor cells, thereby recruiting and activating CD8⁺ T cells via the CCR5/CCL5 axis, ultimately remodeling the TME.
Credit: ©Science China Press
In a groundbreaking study published in the journal National Science Review, researchers from Peking University have introduced a novel strategy to enhance the efficacy of γδ T cells in cancer immunotherapy. γδ T cells, a unique subset of T lymphocytes, have shown potential in allogeneic adoptive cell therapy but face limitations due to low tumor-targeting efficiency. To address this, the team developed antibody-γδ T cell conjugates by metabolic labeling of cell-surface glycans with unnatural sugars containing a bioorthogonal functional group, followed by click reaction to conjugate or glue tumor-targeting antibodies.
The researchers identified cell-surface sialic acids as the optimal site for anchoring antibodies onto γδ T cells and further developed a safe, fast and efficient metabolic glycan labeling strategy to construct antibody-γδ T cell conjugates. The proof-of-concept αPD-L1-γδ T cell conjugate showed promising anti-tumor efficacy both in vitro and in vivo towards PD-L1-positive cancers. Mechanistically, the αPD-L1-γδ T cells targeted cancer cells by binding to PD-L1, inducing pyroptosis—a form of programmed cell death. Additionally, these cells remodeled the tumor microenvironment (TME) to be more immune-active, partly through the recruitment and activation of CD8+ T cells via the CCR5-CCL5 axis. This dual action not only enhances the direct killing of cancer cells but also promotes a more favorable TME for sustained anti-tumor immunity. This work offers a novel therapeutic strategy for solid tumors based on γδ T cells.
This work was led by Prof. Jian Lin, Xing Chen, Hongyan Guo and Long Chen from Peking University. The collaborative team is dedicated to developing cutting-edge chemical biology technologies for advancing tumor immuno-therapies.