Outer Membrane Vesicles From The Gut Microbiome Contribute to Tumor Immunity by Eliciting Cross-Reactive T Cells

Abstract

A growing body of evidence supports the notion that the gut microbiome plays an important role in cancer immunity. However, the underpinning mechanisms remain to be fully elucidated. One attractive hypothesis envisages that among the T cells elicited by the plethora of microbiome proteins a few exist that incidentally recognize neo-epitopes arising from cancer mutations (“molecular mimicry (MM)” hypothesis). To support MM, the human probiotic Escherichia coli Nissle was engineered with the SIINFEKL epitope (OVA-E.coli Nissle) and orally administered to C57BL/6 mice. The treatment with OVA-E.coli Nissle, but not with wild type E. coli Nissle, induced OVA-specific CD8+ T cells and inhibited the growth of tumors in mice challenged with B16F10 melanoma cells expressing OVA. The microbiome shotgun sequencing and the sequencing of TCRs from T cells recovered from both lamina propria and tumors provide evidence that the main mechanism of tumor inhibition is mediated by the elicitation at the intestinal site of cross-reacting T cells, which subsequently reach the tumor environment. Importantly, the administration of Outer Membrane Vesicles (OMVs) from engineered E. coli Nissle, as well as from E. coli BL21(DE3)ΔompA, carrying cancer-specific T cell epitopes also elicited epitope-specific T cells in the intestine and inhibited tumor growth. Overall, our data strengthen the important role of MM in tumor immunity and assign a novel function of OMVs in host-pathogen interaction. Moreover, our results pave the way to the exploitation of probiotics and OMVs engineered with tumor specific-antigens as personalized mucosal cancer vaccines.

Extracellular Vesicles of Probiotics: Shedding Light on the Biological Activity and Future Applications

“…Five studies focused on the correlation between EVs and tumor development ( Table 2 ). Using animal models, Tomasi et al [ 122 ], Luo et al [ 92 ], and Shi et al [ 90 ] tested EVs of E. coli Nissle 1917, A. muciniphila ATCC BAA-835, and L. paracasei PC-H1, respectively. Melanoma, prostate cancer, and colorectal cancer were investigated, and comparable results were obtained despite different routes of administration and dosage; each author reported a reduction in tumor growth.…”

“…In this context, given the results obtained by the authors previously mentioned, it can be assumed that EVs could represent one of the effectors of these processes. For the research of Tomasi et al [ 122 ] it is necessary to highlight that they tested E. coli -EVs engineered with a cancer-specific epitope and showed that the administration of these EVs, but not of wild type EVs, induced a reduction in tumor growth ( Table 2 ). Given these results, we can assume that, unsurprisingly, not all probiotic strains may have the same health-promoting potential, although engineered EVs could represent a promising tool in cancer therapies.…”

“…These studies showed the protective effect of probiotic EVs on atopic dermatitis [ 139 ] and various intestinal pathologies (chemoresistant colorectal cancer [ 140 ] or intestinal infections made by enterotoxigenic E. coli [ 141 ]). It was also noticed that probiotic EVs have a strong immunomodulatory effect on the human body (including the intestines) [ 142 ], and that they can be used in the design of innovative vaccines against infectious diseases [ 143 ] and cancers [ 122 ]. In the last publication, attention was drawn to the participation of prophages in the secretion of EVs by the tested probiotic bacteria [ 144 ].…”

The Value of Microbes in Cancer Neoantigen Immunotherapy

“…Next, researchers took a shotgun sequencing of the microbiome. They sequenced the TCR of T cells and demonstrated that the main reason for tumor suppression was mediated by cross-reactive T cells triggered at the intestinal site [ 95 ]. These findings confirmed that the microbes can trigger T cell cross-reactivity through their own expression of peptides that are highly similar to tumor antigens and thus affect tumor development.…”

Extracellular vesicles from Lactobacillus druckerii inhibit hypertrophic scar fibrosis

“…Bacteria-derived EVs can affect multifarious biological processes [ 19 ]. Bacteria-derived EVs are acknowledged to be proximally or distantly related to many human diseases [ 20 – 22 ]. The role of bacteria-secreted EVs in disease treatment has attracted the attention of researchers.…”