Self‐Blockade of PD‐L1 with Bacteria‐Derived Outer‐Membrane Vesicle for Enhanced Cancer Immunotherapy

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.

Nanodrug enhances post-ablation immunotherapy of hepatocellular carcinoma via promoting dendritic cell maturation and antigen presentation

“…Although thermal ablation (TA) with a great advantage of minimal invasiveness has been widely used for HCC treatment nowadays, most HCC patients eventually die of tumor metastasis and recurrence after ablation [ [3] , [4] , [5] ]. It is well known that thermal ablation can lead to the release of tumor-associated antigens (TAAs) activating antitumor immunological responses, with which the immune checkpoint blockade (ICB) starts to unleash the brake of T cell response for tumor cell killing [ [6] , [7] , [8] , [9] , [10] ]. Hence, the combination of thermal ablation and ICB therapy may be a promising strategy for HCC treatment [ 11 , 12 ].…”

Bacterial outer membrane vesicles and their functionalization as vehicles for bioimaging, diagnosis and therapy

“…Simultaneously, OMVs recruit cytotoxic T lymphocytes and natural killer cells and induce the secretion of INF-γ to enhance antitumor immune responses. 101 The immunosuppressive tumor microenvironment (TME) mediates immune tolerance and evasion in solid tumors, which reduces the efficacy of immunotherapy. By coating the OMV surface with a CaP shell, Qing et al have developed a potent OMVbased strategy for reprogramming the immunosuppressive TME and enhancing cancer immunotherapy.…”

Recent advances in biomedical applications of bacterial outer membrane vesicles

“…Recently, Pan et al developed LyP1-modified OMVs to deliver PD-1 plasmids. 107 These PD-1 plasmid-loaded LyP1-modified OMVs were obtained by extracting OMVs from LyP1-expressed Escherichia coli and encapsulating the PD-1 plasmid. After intravenous injection, these engineered OMVs were efficiently accumulated in tumor tissues through the targeting ability of OMVs LyP1, leading to the expression of PD-1 in tumor cells.…”

“…11 The expression of specific targeting ligands on the surface of OMVs by genetic engineering can further strengthen the targeting effects. 107 PAMPs on OMVs make OMVs more easily recognized and ingested by immune cells, which can be used for targeted drug delivery toward immune cells. Thus, OMVs hold great potential for drug delivery.…”