TY - JOUR
T1 - Bacterial Outer Membrane Vesicles Presenting Programmed Death 1 for Improved Cancer Immunotherapy via Immune Activation and Checkpoint Inhibition
AU - Li, Yao
AU - Zhao, Ruifang
AU - Cheng, Keman
AU - Zhang, Kaiyue
AU - Wang, Yazhou
AU - Zhang, Yinlong
AU - Li, Yujing
AU - Liu, Guangna
AU - Xu, Junchao
AU - Xu, Jiaqi
AU - Anderson, Gregory J.
AU - Shi, Jian
AU - Ren, Lei
AU - Zhao, Xiao
AU - Nie, Guangjun
N1 - Funding Information:
This work was supported by the National Key R&D Program of China (2018YFA0208900, 2018YFE0205300), the National Natural Science Foundation of China (31800838, 31820103004, 31730032, 31800799, U190420008, and 31870994), the Key Research Project of Frontier Science of the Chinese Academy of Sciences (QYZDJ-SSW-SLH022), the Innovation Research Group of National Natural Science Foundation (11621505), the Hundred-Talent Program (Chinese Academy of Sciences), the Beijing Natural Science Foundation of China (Z200020), and the Beijing Nova Program (Z201100006820031).
Publisher Copyright:
©
PY - 2020/12/22
Y1 - 2020/12/22
N2 - 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-Î- A nd T cell-mediated anti-tumor effects in mice. However, IFN-γis 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.
AB - 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-Î- A nd T cell-mediated anti-tumor effects in mice. However, IFN-γis 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.
KW - IFN-Î
KW - NK cells
KW - PD1/PD-L1 blockade
KW - cancer immunotherapy
KW - outer membrane vesicles
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U2 - 10.1021/acsnano.0c03776
DO - 10.1021/acsnano.0c03776
M3 - Article
C2 - 33232124
AN - SCOPUS:85097875446
VL - 14
SP - 16698
EP - 16711
JO - ACS Nano
JF - ACS Nano
SN - 1936-0851
IS - 12
ER -