Systemic Checkpoint Blockade by PD-L1 Single-Chain Antibody Confers Potent Antitumor Immunity and Long-term Survival.

Area of Science:

• Oncology
• Immunology
• Gene Therapy

Background:

• Immune checkpoint inhibitors (ICIs) show promise for solid tumors and hematologic malignancies.
• Current monoclonal antibody (mAb) based ICIs face challenges due to high concentrations, toxicity, and adverse effects.
• The programmed cell death protein-1 (PD-1)-programmed death-ligand 1 (PD-L1) axis is a key target in cancer immunotherapy.

Purpose of the Study:

• To develop a physiologically relevant and systemically stable level of ICIs via genetic antibody engineering.
• To evaluate the efficacy of a recombinant adeno-associated vector (rAAV) expressing PD-L1 single-chain variable fragments (scFv) in preclinical cancer models.

Main Methods:

• Utilized a nonpathogenic, replication-deficient rAAV vector to deliver PD-L1 scFv.
• Tested the rAAV-PD-L1-scFv in syngeneic mouse models of MC38 colorectal and EMT6 breast tumors.
• Assessed CD8+ T-cell function, tumor growth, and immune cell populations within the tumor microenvironment.

Main Results:

• Demonstrated significant protection against PD-L1-mediated inhibition of CD8+ T-cell function.
• Observed reduced growth of primary and secondary tumors, with durable antitumor CD8+ T-cell (CTL) activity.
• Confirmed stable in vivo expression of PD-L1 scFv, leading to increased PD-1- CD8+ T cells and decreased regulatory T cells, M2 macrophages, and myeloid-derived suppressor cells.

Conclusions:

• rAAV-mediated delivery of PD-L1 scFv shows potential as a stable, single-application alternative to traditional mAb therapies.
• This approach effectively enhances anti-tumor immunity by modulating the tumor microenvironment.
• Further development of rAAV-PD-L1-scFv could offer a safer and more effective cancer treatment strategy.