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

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

Research output: Contribution to journalArticle

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-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.

Original languageEnglish (US)
Pages (from-to)16698-16711
Number of pages14
JournalACS Nano
Volume14
Issue number12
DOIs
StatePublished - Dec 22 2020

Keywords

  • cancer immunotherapy
  • IFN-Î
  • NK cells
  • outer membrane vesicles
  • PD1/PD-L1 blockade

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

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