Self-Blockade of PD-L1 with Bacteria-Derived Outer-Membrane Vesicle for Enhanced Cancer Immunotherapy
Jingmei Pan1, Xilin Li1, Binfen Shao2
1Key Laboratory of Advanced Technologies of Materials Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, P. R. China.
Abstract:
The checkpoint inhibitor therapy that blocks programmed death-1 (PD-1) and its major ligand PD-L1 has achieved encouraging clinical efficacy in certain cancers. However, the binding of checkpoint inhibitors with other immune cells that express PD-L1 often results in a low response rate to the blockade and severe adverse effects. Herein, an LyP1 polypeptide-modified outer-membrane vesicle (LOMV) loaded with a PD-1 plasmid is developed to achieve self-blockade of PD-L1 in tumor cells. The nanocarriers accumulate in the tumor tissue through OMV-targeting ability and are internalized into the tumor cells via the LyP1-mediated target, subsequently delivering PD-1 plasmid into the nucleus, leading to the expression of PD-1 by the tumor cells. In addition, a magnetic particle chemiluminescence kit is developed to quantitatively detect the binding rate of PD-1/PD-L1. The self-expressed PD-1 bonded with the PD-L1 is expressed by both autologous and neighboring tumor cells, achieving self-blockade. Simultaneously, the outer-membrane protein of LOMV recruits cytotoxic lymphocyte cells and natural killer cells to tumor tissues and stimulates them to secrete IFN-γ , improving the antitumor activity of the PD-1/PD-L1 self-blocking therapy.
Insights
This study introduces a novel nanocarrier system for cancer therapy. It engineers tumor cells to express programmed death-1 (PD-1) for self-blockade of PD-L1, enhancing antitumor immunity.
Area of Science:
- Biomedical Engineering
- Immunotherapy
- Nanotechnology
Background:
- Checkpoint inhibitor therapy targeting programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) shows efficacy in cancers.
- Off-target binding of inhibitors to immune cells limits response rates and causes adverse effects.
Purpose of the Study:
- To develop a novel nanocarrier system for enhanced cancer immunotherapy.
- To achieve self-blockade of PD-L1 in tumor cells using engineered PD-1 expression.
- To improve the antitumor activity and reduce side effects of checkpoint blockade therapy.
Main Methods:
- Development of LyP1 polypeptide-modified outer-membrane vesicles (LOMVs) loaded with PD-1 plasmid.
- Tumor-targeting delivery of PD-1 plasmid via LOMVs for intracellular expression.
- Utilizing a magnetic particle chemiluminescence kit for quantitative PD-1/PD-L1 binding detection.
- Assessment of LOMV-mediated recruitment of immune cells and cytokine secretion.
Main Results:
- LOMVs successfully delivered PD-1 plasmid into tumor cells, leading to self-expressed PD-1.
- Engineered tumor cells achieved self-blockade by binding to PD-L1 on autologous and neighboring cells.
- LOMV outer-membrane proteins recruited cytotoxic lymphocytes and natural killer cells, stimulating IFN-γ secretion.
- Enhanced antitumor activity was observed through combined PD-1/PD-L1 self-blocking and immune cell recruitment.
Conclusions:
- The LOMV system offers a promising strategy for self-blockade of PD-1/PD-L1 in cancer therapy.
- This approach enhances antitumor immunity by modulating the tumor microenvironment and reducing off-target effects.
- The developed nanocarrier system holds potential for improving the efficacy and safety of cancer immunotherapy.
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