Bacterial Outer Membrane Vesicles Presenting Programmed Death 1 for Improved Cancer Immunotherapy via Immune Activation and Checkpoint Inhibition.

Abstract

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-γ- and T cell-mediated anti-tumor effects in mice. However, IFN-γ 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.

• Authors: Yao Li, Ruifang Zhao, Keman Cheng, Kaiyue Zhang, Yazhou Wang, Yinlong Zhang, Yujing Li, Guangna Liu, Junchao Xu, Jiaqi Xu, Gregory J Anderson, Jian Shi, Lei Ren, Xiao Zhao, Guangjun Nie
• Journal: ACS nano (ACS Nano) Vol. 14 Issue 12 Pg. 16698-16711 (Dec 22 2020) ISSN: 1936-086X [Electronic] United States
• PMID: 33232124 (Publication Type: Journal Article)