HMGB1/GPC3 dual targeting vaccine induces dendritic cells-mediated CD8+T cell immune response and elicits potential therapeutic effect in hepatocellular carcinoma

Shi, Xiaoqing; Ding, Jiage; Zheng, Yanyan; Wang, Jiawei; Sobhani, Navid; Neeli, Praveen Kumar; Wang, Gang; Zheng, Junnian; Chai, Dafei

doi:10.1016/j.isci.2023.106143

Cited by 6 publications

(3 citation statements)

References 42 publications

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“…The GAPDH antibody (Cell Signaling, #5174, used at 1:1000), host species rabbit, recognized only the expected band at 37 kDa on western blots of mouse brains. This is consistent with previous reports of GAPDH use in western blotting (Levenga et al, 2017, 2021; Shi et al, 2023).…”

Section: Methodssupporting

confidence: 93%

AKT2 modulates astrocytic nicotine responsesin vivo

Lombardi,

Wong,

Bower

et al. 2024

Preprint

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A better understanding of nicotine neurobiology is needed to reduce or prevent chronic addiction, ameliorate the detrimental effects of nicotine withdrawal, and increase successful cessation of use. Nicotine binds and activates two astrocyte-expressed nicotinic acetylcholine receptors (nAChRs), α4β2 and α7. We recently found thatProtein kinase B-β (Pkb-β orAkt2) expression is restricted to astrocytes in mice and humans. To determine if AKT2 plays a role in astrocytic nicotinic responses, we generated astrocyte-specificAkt2conditional knockout (cKO) and fullAkt2KO mice forin vivoandin vitroexperiments. Forin vivostudies, we examined mice exposed to chronic nicotine for two weeks in drinking water (200 μg/mL) and following acute nicotine challenge (0.09, 0.2 mg/kg) after 24 hrs. Ourin vitrostudies used cultured mouse astrocytes to measure nicotine-dependent astrocytic responses. We validated our approaches using lipopolysaccharide (LPS) exposure inducing astrogliosis. Sholl analysis was used to measure glial fibrillary acidic protein responses in astrocytes. Our data show that wild-type (WT) mice exhibit increased astrocyte morphological complexity during acute nicotine exposure, with decreasing complexity during chronic nicotine use, whereasAkt2cKO mice showed increased astrocyte morphology complexity. In culture, we found that 100μM nicotine was sufficient for morphological changes and blocking α7 or α4β2 nAChRs prevented observed morphologic changes. Finally, we performed conditioned place preference (CPP) inAkt2cKO mice and found that astrocytic AKT2 deficiency reduced nicotine preference compared to controls. These findings show the importance of nAChRs andAkt2signaling in the astrocytic response to nicotine.Main PointsNicotine regulates astrogliosisin vivo: acute exposure boosts complexity; chronic exposure diminishes it.AKT2, expressed in astroglia, modulates morphological changes in response to nicotine and nicotine-dependent conditioned place preference.

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Section: Methodssupporting

confidence: 93%

AKT2 modulates astrocytic nicotine responsesin vivo

Lombardi,

Wong,

Bower

et al. 2024

Preprint

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“…These results strongly suggested the induction of memory CD8 + T cell responses by LNP-pE285K-mAb against the p53 E285K antigen. To provide anti-tumor immunity, transiently stimulated CD8 + T cells undergo unusually rapid bursts of numerous cell divisions and form quiescent, long-lived memory cells that remain poised to reproliferate following subsequent immunological challenges [ 41 ]. In this regard, we examined the subsets of memory CD8 + T cells (naïve CD44 low CD62L high CD8 + T cells, CD8 + T N ; central memory CD44 high CD62L high CD8 + T cells, CD8T CM ; effector memory CD44 high CD62L low CD8 + T cells, CD8 + T EM ) 35 days after tumor challenge using FACS analysis based on CD44 and CD62L markers.…”

Section: Resultsmentioning

confidence: 99%

Remodeling of anti-tumor immunity with antibodies targeting a p53 mutant

Chai,

Wang,

Fan

et al. 2024

J Hematol Oncol

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Background p53, the most frequently mutated gene in cancer, lacks effective targeted drugs. Methods We developed monoclonal antibodies (mAbs) that target a p53 hotspot mutation E285K without cross-reactivity with wild-type p53. They were delivered using lipid nanoparticles (LNPs) that encapsulate DNA plasmids. Western blot, BLI, flow cytometry, single-cell sequencing (scRNA-seq), and other methods were employed to assess the function of mAbs in vitro and in vivo. Results These LNP-pE285K-mAbs in the IgG1 format exhibited a robust anti-tumor effect, facilitating the infiltration of immune cells, including CD8+ T, B, and NK cells. scRNA-seq revealed that IgG1 reduces immune inhibitory signaling, increases MHC signaling from B cells to CD8+ T cells, and enriches anti-tumor T cell and B cell receptor profiles. The E285K-mAbs were also produced in the dimeric IgA (dIgA) format, whose anti-tumor activity depended on the polymeric immunoglobulin receptor (PIGR), a membrane Ig receptor, whereas that of IgG1 relied on TRIM21, an intracellular IgG receptor. Conclusions Targeting specific mutant epitopes using DNA-encoded and LNP-delivered mAbs represents a potential precision medicine strategy against p53 mutants in TRIM21- or PIGR-positive cancers.

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“…The designed DNA vaccine can specifically express the antigen of interest or integrate genes encoding multiple antigens into a plasmid, providing immune protection against multiple diseases. For instance, DNA vaccine can be introduced with chimeric cytokine genes as adjuvants into the antigen plasmid, allowing for co-expression and enhanced immune responses ( 20 , 21 ). Furthermore, specific motifs on the DNA construct can induce immunostimulatory effects, even in the absence of antigen-coding genes ( 22 ).…”

Section: Current Status and Challenges Of Dna Vaccinementioning

confidence: 99%

The next-generation DNA vaccine platforms and delivery systems: advances, challenges and prospects

Lu,

Lim,

et al. 2024

Front. Immunol.

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Vaccines have proven effective in the treatment and prevention of numerous diseases. However, traditional attenuated and inactivated vaccines suffer from certain drawbacks such as complex preparation, limited efficacy, potential risks and others. These limitations restrict their widespread use, especially in the face of an increasingly diverse range of diseases. With the ongoing advancements in genetic engineering vaccines, DNA vaccines have emerged as a highly promising approach in the treatment of both genetic diseases and acquired diseases. While several DNA vaccines have demonstrated substantial success in animal models of diseases, certain challenges need to be addressed before application in human subjects. The primary obstacle lies in the absence of an optimal delivery system, which significantly hampers the immunogenicity of DNA vaccines. We conduct a comprehensive analysis of the current status and limitations of DNA vaccines by focusing on both viral and non-viral DNA delivery systems, as they play crucial roles in the exploration of novel DNA vaccines. We provide an evaluation of their strengths and weaknesses based on our critical assessment. Additionally, the review summarizes the most recent advancements and breakthroughs in pre-clinical and clinical studies, highlighting the need for further clinical trials in this rapidly evolving field.

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HMGB1/GPC3 dual targeting vaccine induces dendritic cells-mediated CD8+T cell immune response and elicits potential therapeutic effect in hepatocellular carcinoma

Cited by 6 publications

References 42 publications

AKT2 modulates astrocytic nicotine responsesin vivo

AKT2 modulates astrocytic nicotine responsesin vivo

Remodeling of anti-tumor immunity with antibodies targeting a p53 mutant

The next-generation DNA vaccine platforms and delivery systems: advances, challenges and prospects

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