Journal
ACS NANO
Volume 14, Issue 12, Pages 16698-16711Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.0c03776
Keywords
outer membrane vesicles; PD1/PD-L1 blockade; cancer immunotherapy; IFN-gamma; NK cells
Categories
Funding
- National Key R&D Program of China [2018YFA0208900, 2018YFE0205300]
- National Natural Science Foundation of China [31800838, 31820103004, 31730032, 31800799, U190420008, 31870994]
- Key Research Project of Frontier Science of the Chinese Academy of Sciences [QYZDJ-SSW-SLH022]
- Innovation Research Group of National Natural Science Foundation [11621505]
- Hundred-Talent Program (Chinese Academy of Sciences)
- Beijing Natural Science Foundation of China [Z200020]
- Beijing Nova Program [Z201100006820031]
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Natural, extracellular membrane vesicles secreted by Gram-negative bacteria, outer membrane vesicles (OMVs), contain numerous pathogen-associated molecular patterns which can activate systemic immune responses. Previous studies have shown that OMVs induce strong IFN-gamma- and T cell-mediated anti-tumor effects in mice. However, IFN-gamma is known to upregulate immunosuppressive factors in the tumor microenvironment, especially the immune checkpoint programmed death 1 ligand 1 (PD-L1), which may hamper T cell function and limit immunotherapeutic effectiveness. Here, we report the development of genetically engineered OMVs whose surface has been modified by insertion of the ectodomain of programmed death 1 (PD1). This genetic modification does not affect the ability of OMVs to trigger immune activation. More importantly, the engineered OMV-PD1 can bind to PD-L1 on the tumor cell surface and facilitate its internalization and reduction, thereby protecting T cells from the PD1/PD-L1 immune inhibitory axis. Through the combined effects of immune activation and checkpoint suppression, the engineered OMVs drive the accumulation of effector T cells in the tumor, which, in turn, leads to a greater impairment of tumor growth, compared with not only native OMVs but also the commonly used PD-L1 antibody. In conclusion, this work demonstrates the potential of bioengineered OMVs as effective immunotherapeutic agents that can comprehensively regulate the tumor immune microenvironment to effect markedly increased anti-tumor efficacy.
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