Macrophage-mediated tumor-targeted delivery of engineered Salmonella typhimurium VNP20009 in anti-PD1 therapy against melanoma

Wu, Leyang; Li, Lin; Li, Shufeng; Liu, Lina; Xin, Wenjie; Li, Chenyang; Yin, Xingpeng; Xu, Xuebo; Bao, Feifei; Hua, Zichun

doi:10.1016/j.apsb.2022.05.006

Cited by 26 publications

(27 citation statements)

References 73 publications

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“…The novel attenuated Salmonella mutant, Δ htrA ‐VNP, which we described before, was used as an expression vector, given its superior safety (Zhang et al, 2016 ). A major advantage of using Salmonella as a vaccine carrier is that it can survive and proliferate in macrophages for a period of time and maintain metabolic activity to achieve more precise and effective delivery of target antigens to macrophages (Rao et al, 2020 ; Wu, Li, et al, 2022 ). To determine whether Δ htrA ‐VNP has similar effects, we examined the proliferation and survival of wild‐type VNP (wt‐VNP) and Δ htrA ‐VNP in macrophages.…”

Section: Resultsmentioning

confidence: 99%

“…The precipitate bacterial cells were resuspended in 5 ml of PBS, broken ultrasonically at 300 W on ice for 15 min (5‐s sonication; 5‐s interval) to collect the bacterial total protein, and then centrifuged at 13,000 rpm for 10 min, and total protein in the precipitated bacteria was contained in the supernatant. Proteins were collected from the supernatant obtained in the first step according to the trichloroacetic acid protein precipitation protocol (Wu, Li, et al, 2022 ). The method for collecting proteins expressed by engineered attenuated Salmonella strains induced in cells is described below.…”

Section: Methodsmentioning

confidence: 99%

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A SARS-CoV-2 oral vaccine development strategy based on the attenuated Salmonella type III secretion system

Yin

et al. 2022

Journal of Applied Microbiology

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Aims This study aimed to provide a safe, stable and efficient SARS‐CoV‐2 oral vaccine development strategy based on the type III secretion system of attenuated Salmonella and a reference for the development of a SARS‐CoV‐2 vaccine. Methods and Results The attenuated Salmonella mutant Δ htrA ‐VNP was used as a vector to secrete the antigen SARS‐CoV‐2 based on the type III secretion system (T3SS). The Salmonella pathogenicity island 2 (SPI‐2)‐encoded T3SS promoter (sifB) was screened to express heterologous antigens (RBD, NTD, S2), and the SPI‐2‐encoded secretion system (sseJ) was employed to secrete this molecule (psifB‐sseJ‐antigen, abbreviated BJ‐antigen). Both immunoblotting and fluorescence microscopy revealed effective expression and secretion of the antigen into the cytosol of macrophages in vitro. The mixture of the three strains (BJ‐RBD/NTD/S2, named AisVax) elicited a marked increase in the induction of IgA or IgG S‐protein Abs after oral gavage, intraperitoneal and subcutaneous administration. Flow cytometric analysis proved that AisVax caused T‐cell activation, as shown by a significant increase in CD44 and CD69 expression. Significant production of IgA or IgG N‐protein Abs was also detected by using psifB‐sseJ‐N(FL), indicating the universality of this strategy. Conclusions Delivery of multiple SARS‐CoV‐2 antigens using the type III secretion system of attenuated Salmonella Δ htrA ‐VNP is a potential COVID‐19 vaccine strategy. Significance and Impact of the Study The attenuated Salmonella strain Δ htrA ‐VNP showed excellent performance as a vaccine vector. The Salmonella SPI‐2‐encoded T3SS showed highly efficient delivery of SARS‐COV‐2 antigens. Anti‐loss elements integrated into the plasmid stabilized the phenotype of the vaccine strain. Mixed administration of antigen‐expressing strains improved antibody induction.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

A SARS-CoV-2 oral vaccine development strategy based on the attenuated Salmonella type III secretion system

Yin

et al. 2022

Journal of Applied Microbiology

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“…Recently, an inflammatory cell death known as pyroptosis has emerged as an important mediator of the inflammatory response, and as research progresses, pyroptosis is being proven to be closely associated with an increasing number of types of inflammatory diseases and tumors [10,57,58]. Although several recent studies have expanded on the involvement of gasdermin family genes in pyroptosis pathways [59][60][61], the GSDMD-mediated pyroptosis signaling pathway triggered by inflammasomes has been shown to be the pathway most associated with the formation of an immunosuppressive microenvironment in a variety of tumors [62].…”

Section: Discussionmentioning

confidence: 99%

“…Except for DFNB59, the pyroptosis-mediating ability of all members has been well validated [7]. The inflammatory response caused by pyroptosis promotes immune cell infiltration to eliminate the pathogen or activate the tumor microenvironment [8][9][10]. However, excessive inflammatory responses not only damage normal cells but also reduce immune surveillance and the suppression of malignant cells, resulting in chronic inflammation and tumor immune escape [11].…”

Section: Introductionmentioning

confidence: 99%

Bulk and Single-Cell Transcriptome Analyses Revealed That the Pyroptosis of Glioma-Associated Macrophages Participates in Tumor Progression and Immunosuppression

Yin

et al. 2022

Oxidative Medicine and Cellular Longevity

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Glioma is the most common of all central nervous system (CNS) malignancies and is associated with a poor prognosis. Pyroptosis has been proven to be associated with the progression of multiple tumors and CNS diseases. However, the relationships between pyroptosis and clinical prognosis and immune cell infiltration are unclear in glioma. In this study, we conducted a comprehensive exploration of pyroptosis in glioma. First, prognosis-related genes were screened at each key regulatory locus in the pyroptosis pathway, and the prognostic ability and coexpression relationships of GSDMD and its upstream pathway genes NLRC4/CASP1/CASP4 were identified and well validated in multiple datasets. Tissue microarray-based immunohistochemistry results showed higher levels of NLRC4 and N-terminal GSDMD in high-grade gliomas, providing conclusive evidence of pyroptosis in gliomas. The robustness of the prognostic model based on these four genes was well validated in TCGA and CGGA cohorts. Bulk RNA-seq-based analysis showed that the group defined as the high-risk group according to the model showed activation of multiple inflammatory response pathways and impaired synaptic gene expression and had a higher infiltration of bone marrow-derived macrophages (BMDMs) and a hypersuppressed immune microenvironment. More importantly, three independent single-cell RNA-seq (scRNA-seq) datasets demonstrated that tumor-infiltrating macrophages, particularly BMDMs but not tissue-resident microglia, showed significant coexpression of the GSDMD and CASP genes, and BMDMs from high-grade gliomas accounted for a higher proportion of immune infiltrating cells and had higher expression of pyroptosis genes. Finally, we revealed the activation of pathways in response to LPS/bacteria and oxidative stress during BMDM development toward the pyroptosis cell fate by pseudotime trajectory analysis, suggesting potential BMDM pyroptosis initiators. The above results provide not only novel insights into the pathological mechanisms of glioma but also novel therapeutic targets for glioma, suggesting the potential application of pyroptosis inhibitors (e.g., disulfiram).

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“…In antitumor therapy with VNP, the accumulation of strains within the tumor significantly induces the infiltration of macrophages, , which can clear pathogenic microorganisms by direct phagocytosis. , Phagocytosis of excess bacteria triggers pyroptosis in macrophages and the release of inflammatory factors to recruit more macrophages for more efficient strain clearance . Although macrophages are essential in the systemic temperature regulation of the body, little is known about whether VNP will lead to specific changes in macrophages, e.g.…”

Section: Introductionmentioning

confidence: 99%

Combined Cellular Thermometry Reveals That Salmonella typhimurium Warms Macrophages by Inducing a Pyroptosis-like Phenotype

Chen

Chang

et al. 2022

J. Am. Chem. Soc.

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The attenuated Salmonella typhimurium VNP20009, enriched in tumors, is known to have antitumor effects and recruit macrophages. Little is known, however, about whether VNP will lead to specific changes in macrophages, e.g., cell temperature. Here, using a real-time wireless multicell thermometry system, we reported for the first time that VNP20009 increases the macrophage temperature by 0.2 °C. Nigericin, recognized as an inducer of pyroptosis, was found to induce macrophage warming. Moreover, the ΔsipD-VNP20009 strain failed to induce macrophage pyroptosis and simultaneously failed to warm macrophages, and the Gsdmd −/− macrophages that were unable to achieve pyroptosis were no longer warmed following VNP20009 induction. These results suggested that the occurrence of macrophage pyroptosis is the key to VNP20009-mediated cell warming. With the aid of a single-cell thermometry system, it was further confirmed that cell warming occurred in pyroptosis-like macrophages. Cellular warming was not detected after the induction of pyroptosis in macrophages with loss of mitochondrial biological function, suggesting a critical role of mitochondria in warming. Moreover, we found that VNP20009 caused local tumor temperature increases. The local tumor warming induced by VNP20009 was significantly reduced after macrophage clearance. Notably, this temperature increase contributed to M1-type polarization. These findings expanded our knowledge of the cellular biological changes induced by the strain on macrophages, as well as the biochemical phenomena accompanying pyroptosis, and provide a reference for the study of biochemical signals transduced to biothermal signals with a combined cell-level temperature detector.

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Macrophage-mediated tumor-targeted delivery of engineered Salmonella typhimurium VNP20009 in anti-PD1 therapy against melanoma

Cited by 26 publications

References 73 publications

A SARS-CoV-2 oral vaccine development strategy based on the attenuated Salmonella type III secretion system

A SARS-CoV-2 oral vaccine development strategy based on the attenuated Salmonella type III secretion system

Bulk and Single-Cell Transcriptome Analyses Revealed That the Pyroptosis of Glioma-Associated Macrophages Participates in Tumor Progression and Immunosuppression

Combined Cellular Thermometry Reveals That Salmonella typhimurium Warms Macrophages by Inducing a Pyroptosis-like Phenotype

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