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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Engineered Bacterial Outer Membrane Vesicles as Controllable Two-Way Adaptors to Activate Macrophage Phagocytosis for
Qingqing Feng1, Xiaotu Ma1, Keman Cheng1
1CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 11 Beiyitiao, Zhongguancun, Beijing, 100190, China.
Abstract:
The most immune cells infiltrating tumor microenvironment (TME), tumor-associated macrophages (TAMs) closely resemble immunosuppressive M2-polarized macrophages. Moreover, tumor cells exhibit high expression of CD47 "don't eat me" signal, which obstructs macrophage phagocytosis. The precise and efficient activation of TAMs is a promising approach to tumor immunotherapy; however, re-education of macrophages remains a challenge. Bacteria-derived outer membrane vesicles (OMVs) are highly immunogenic nanovesicles that can robustly stimulate macrophages. Here, an OMV-based controllable two-way adaptor is reported, in which a CD47 nanobody (CD47nb) is fused onto OMV surface (OMV-CD47nb), with the outer surface coated with a polyethylene glycol (PEG) layer containing diselenide bonds (PEG/Se) to form PEG/Se@OMV-CD47nb. The PEG/Se layer modification not only mitigates the immunogenicity of OMV-CD47nb, thereby remarkedly increasing the dose that can be administered safely through intravenous injection, but also equips the formulation with radiation-triggered controlled release of OMV-CD47nb. Application of radiation to tumors in mice injected with the nanoformulation results in remodeling of TME. As two-way adaptors, OMV-CD47nb activates TAM phagocytosis of tumor cells via multiple pathways, including induction of M1 polarization and blockade of "don't eat me" signal. Moreover, this activation of TAMs results in the stimulation of T cell-mediated antitumor immunity through effective antigen presentation.
Insights
Engineered bacteria outer membrane vesicles (OMVs) target CD47 on tumor cells, reprogramming immunosuppressive macrophages. Radiation triggers controlled release, enhancing anti-tumor immunity via T cell activation.
Area of Science:
- Immunology
- Nanotechnology
- Cancer Therapy
Background:
- Tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) often exhibit immunosuppressive M2 polarization.
- Tumor cells express CD47, a "don't eat me" signal, inhibiting macrophage phagocytosis and hindering anti-tumor responses.
- Re-educating macrophages for effective tumor immunotherapy remains a significant challenge.
Purpose of the Study:
- To develop a novel OMV-based nano-adaptor for controlled activation of TAMs and enhanced anti-tumor immunity.
- To investigate the efficacy of a radiation-triggered, dual-action system for overcoming macrophage suppression and tumor cell evasion.
Main Methods:
- Construction of OMV-CD47 nanobodies (OMV-CD47nb) fused with a CD47 nanobody.
- Modification of OMV-CD47nb with a polyethylene glycol (PEG) layer containing diselenide bonds (PEG/Se) for controlled release (PEG/Se@OMV-CD47nb).
- Evaluation of the nanoformulation's immunomodulatory effects and anti-tumor efficacy in a murine model following radiation treatment.
Main Results:
- The PEG/Se layer mitigated OMV immunogenicity, allowing safe intravenous administration and enabling radiation-triggered release.
- PEG/Se@OMV-CD47nb successfully induced M1 polarization of TAMs and blocked the CD47 "don't eat me" signal, promoting phagocytosis.
- The activated TAMs enhanced T cell-mediated anti-tumor immunity through improved antigen presentation.
Conclusions:
- The developed OMV-based nano-adaptor represents a promising strategy for reprogramming the TME and overcoming macrophage-mediated immunosuppression.
- Radiation-triggered controlled release of OMV-CD47nb offers a targeted approach to activate TAMs and stimulate effective anti-tumor immune responses.
- This dual-action immunotherapy holds potential for advancing cancer treatment by harnessing the immune system against tumors.
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