Bacterial cytoplasmic membranes synergistically enhance the antitumor activity of autologous cancer vaccines

Abstract

Cancer vaccines based on resected tumors from patients have gained great interest as an individualized cancer treatment strategy. However, eliciting a robust therapeutic effect with personalized vaccines remains a challenge because of the weak immunogenicity of autologous tumor antigens. Utilizing exogenous prokaryotic constituents that act as adjuvants to enhance immunogenicity is a promising strategy to overcome this limitation. However, nonspecific stimulation of the immune system may elicit an undesirable immunopathological state. To specifically trigger sufficient antitumor reactivity without notable adverse effects, we developed an antigen and adjuvant codelivery nanoparticle vaccine based on Escherichia coli cytoplasmic membranes (EMs) and tumor cell membranes (TMs) from resected autologous tumor tissue. Introduction of the EM into the hybrid membrane nanoparticle vaccines (HM-NPs) induced dendritic cell maturation, thus activating splenic T cells. HM-NPs showed efficacy in immunogenic CT26 colon and 4T1 breast tumor mouse models and also efficiently induced tumor regression in B16-F10 melanoma and EMT6 breast tumor mouse models. Furthermore, HM-NPs provoked a strong tumor-specific immune response, which not only extended postoperative animal survival but also conferred long-term protection (up to 3 months) against tumor rechallenge in a CT26 colon tumor mouse model. Specific depletion of different immune cell populations revealed that CD8+ T and NK cells were crucial to the vaccine-elicited tumor regression. Individualized autologous tumor antigen vaccines based on effective activation of the innate immune system by bacterial cytoplasmic membranes hold great potential for personalized treatment of postoperative patients with cancer.

E. coli Membrane Vesicles as a Catalase Carrier for Long-Term Tumor Hypoxia Relief to Enhance Radiotherapy

“…We examined the molecular composition of EMs proteins through SDS-PAGE assay (Figure S5c) and subjected proteins in EMs to proteomic identification by mass spectrometry (Figure S5d). We analyzed the relative abundance of potential adjuvants in the total protein, including flagellin (FliC), outer membrane protein A (OmpA), phosphatidylserine decarboxylase (Psd), and 18 kinds of lipoproteins. − These various PAMPs in EMs could guarantee their ability in better immune activation than single component synergistically.…”

Dendritic Cell-Based Immunotherapy in Hot and Cold Tumors

“…They vaccinated tumor-bearing mice with the nanoparticles and showed improved activation of DCs and Ag-specific T cells. The nanoparticle vaccination enhanced mouse survival and provided a long-term anti-tumor effect [184]. Similar to stimulation by bacteria, tumor inflammation stimulated by a virus enhances the efficacy of DC vaccines.…”

Rapid Surface Display of mRNA Antigens by Bacteria‐Derived Outer Membrane Vesicles for a Personalized Tumor Vaccine

“…Using HEK293derived TLR reporter cells, [30] we found that OMV-LL significantly activated TLR2, TLR4, and TLR5 and slightly activated TLR9 (Figure 2B,C), which can be activated by lipoproteins, lipopolysaccharide (LPS), flagellin, and microbial genomic DNA, respectively, all of which are expected to be present in bacteria-derived OMVs. [29,31] Next, we evaluated the innate immunity stimulation and antigen presentation induced by our OMV-based mRNA vaccine in BMDCs. We synthesized mRNA encoding an antigenic epitope of ovalbumin (257-SIINFEKL-264, OVA; mRNA OVA ) and used OMV-L (OMV-L-mRNA OVA ) or OMV-LL (OMV-LL-mRNA OVA ) to deliver it.…”