An all-in-one adjuvanted therapeutic cancer vaccine targeting dendritic cell cytosol induces long-lived tumor suppression through NLRC4 inflammasome activation

Puth, Sao; Verma, Vivek; Hong, Seol Hee; Tan, Wenzhi; Lee, Shee Eun; Rhee, Joon Haeng

doi:10.1016/j.biomaterials.2022.121542

Cited by 14 publications

(13 citation statements)

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“…To assess the therapeutic efficacy of the mHTV, a cancer mouse model was established by implanting TC‐1 tumor cells expressing HPV type 16 E6 and E7 oncoproteins as previously described 27,28 . TC‐1 tumor‐bearing mice were immunized with mHTV in the contralateral leg or peritumoral region via the I.M or S.C route, respectively, at 5‐ and 6‐day intervals (Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

“…[21][22][23][24] Therefore, immunotherapy using DNA, peptides, and DCs has been developed to target E6/E7 subtypes of high-risk HPV serotypes as a potential treatment for cervical intraepithelial neoplasia and early-stage cancers. [25][26][27][28][29][30] We previously developed a promising mRNA platform and confirmed the strong immune response of an mRNA vaccine. 14,15 The mRNA-HPV therapeutic vaccine (mHTV) lacks oncogenicity and efficiently expresses E6 and E7 oncoproteins derived from pathogenic HPV 16 and 18 strains.…”

Section: Introductionmentioning

confidence: 93%

“…To assess the therapeutic efficacy of the mHTV, a cancer mouse model was established by implanting TC-1 tumor cells expressing HPV type 16 E6 and E7 oncoproteins as previously described. 27,28 TC-1 tumor-bearing mice were immunized with mHTV in the contralateral leg or peritumoral region via the I.M or S.C route, respectively, at 5-and 6-day intervals (Figure 3A). The mHTV-immunized mice exhibited significantly higher levels of tetramer-positive T cells in whole blood (Figure 3B and These experiments used the same immunization schedule and doses as in Figure 3 and were performed with a different lot, but only mHTV reduced tumor size, demonstrating that the antitumor effect of mHTV is antigenspecific.…”

Section: Mhtv Exhibits Therapeutic Efficacy In a Tc-1 Murine Modelmentioning

confidence: 99%

“…Notably, E6 and E7 proteins from high‐risk HPV serotypes 16 and 18 exert a significant influence on the cell cycle and immortalize infected cells by degrading the p53 and retinoblastoma protein 21–24 . Therefore, immunotherapy using DNA, peptides, and DCs has been developed to target E6/E7 subtypes of high‐risk HPV serotypes as a potential treatment for cervical intraepithelial neoplasia and early‐stage cancers 25–30 …”

Section: Introductionmentioning

confidence: 99%

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mRNA‐HPV vaccine encoding E6 and E7 improves therapeutic potential for HPV‐mediated cancers via subcutaneous immunization

Lee,

Yoon,

Hong

et al. 2023

Journal of Medical Virology

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The E6 and E7 proteins of specific subtypes of human papillomavirus (HPV), including HPV 16 and 18, are highly associated with cervical cancer as they modulate cell cycle regulation. The aim of this study was to investigate the potential antitumor effects of a messenger RNA‐HPV therapeutic vaccine (mHTV) containing nononcogenic E6 and E7 proteins. To achieve this, C57BL/6j mice were injected with the vaccine via both intramuscular and subcutaneous routes, and the resulting effects were evaluated. mHTV immunization markedly induced robust T cell‐mediated immune responses and significantly suppressed tumor growth in both subcutaneous and orthotopic tumor‐implanted mouse model, with a significant infiltration of immune cells into tumor tissues. Tumor retransplantation at day 62 postprimary vaccination completely halted progression in all mHTV‐treated mice. Furthermore, tumor expansion was significantly reduced upon TC‐1 transplantation 160 days after the last immunization. Immunization of rhesus monkeys with mHTV elicited promising immune responses. The immunogenicity of mHTV in nonhuman primates provides strong evidence for clinical application against HPV‐related cancers in humans. All data suggest that mHTV can be used as both a therapeutic and prophylactic vaccine.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

Section: Mhtv Exhibits Therapeutic Efficacy In a Tc-1 Murine Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

mRNA‐HPV vaccine encoding E6 and E7 improves therapeutic potential for HPV‐mediated cancers via subcutaneous immunization

Lee,

Yoon,

Hong

et al. 2023

Journal of Medical Virology

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“…Flagellin is also an important immunologic adjuvant, which can trigger MyD88-dependent and MyD88-independent pathways to send signals and activate nuclear factors NF-κB by recognizing TLR5 ( Toll like receptor 5) and NOD like receptor, inducing the production of various cytokines and chemokines, activating the body's innate immune system, and enhancing the body's adaptive immunity to the target antigen (Song, et al 2017). Flagellin adjuvants are widely used in the research of vaccines against in uenza, cancer, AIDS, newcastle disease, COVID-19, and other diseases (Puth, et al 2022;Barkhordari, et al 2021;Jiang, et al 2021;Pulendran, et al 2021;Hinkula, et al 2019). Due to differences in the structure of agellin from different bacterial species, agellin may contain 2-4 different structural domains (D0, D1, D2, and D3).…”

Section: Introductionmentioning

confidence: 99%

Studies on the structure and stimulating effect on Caco-2 cells of flagellin and its truncated proteins of Escherichia coli Nissle 1917

Ou²,

Wen

et al. 2023

Preprint

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This study aimed to investigate the structural characteristics and their effects on stimulating Caco-2 cells of Escherichia coli Nissle 1917 flagellin (FliCEcN) and its truncated proteins, FliC△174−506 (D2-D3 domain deleted) and FliC△274−406 (D3 domain deleted). The experiment predicted the tertiary structure of FliCEcN by Alphofold2, analyzed the structural characteristics of FliCEcN, FliC△174−506 and FliC△274−406 by surface-enhanced Raman spectroscopy (SERS) and circular dichroism (CD), and detected the secretion levels of IL-6 (interleukin-6), IL-10 (interleukin-10) and TNF-α (tumor necrosis factor-α) after FliCEcN, FliC△174−506 and FliC△274−406 stimulated Caco-2 cells for 6 and 12 h, respectively. The results showed that the NH3-ends and COOH-ends of FliCEcN were highly conserved, mainly composed of α-helix; the middle domains were highly variable, mainly composed of β-sheet and random coil. The Raman peaks of FliC△174−506 and FliC△274−406 generally maintained the main chain peaks of FliCEcN, while the side chain and amino acid peaks were absent to varying degrees. The composition of the secondary structure of FliC△174−506 and FliC△274−406 was altered. FliCEcN, FliC△174−506 and FliC△274−406 stimulated Caco-2 cells to secrete cytokines IL-10, IL-6 and TNF-α differently. The complete FliCEcN structure could stimulate more secretion of IL-10; the FliC△174−506 group had higher secretion of IL-6; and the FliC△274−406 group had higher secretion of TNF-α. In conclusion, deletion of different domains of the hypervariable region of FliCEcN affects its SERS and CD spectrum and stimulates Caco-2 cells to secrete cytokines.

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Inflammasome: structure, biological functions, and therapeutic targets

Dai,

Zhou,

Shi

2023

MedComm

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Inflammasomes are a group of protein complex located in cytoplasm and assemble in response to a wide variety of pathogen‐associated molecule patterns, damage‐associated molecule patterns, and cellular stress. Generally, the activation of inflammasomes will lead to maturation of proinflammatory cytokines and pyroptotic cell death, both associated with inflammatory cascade amplification. A sensor protein, an adaptor, and a procaspase protein interact through their functional domains and compose one subunit of inflammasome complex. Under physiological conditions, inflammasome functions against pathogen infection and endogenous dangers including mtROS, mtDNA, and so on, while dysregulation of its activation can lead to unwanted results. In recent years, advances have been made to clarify the mechanisms of inflammasome activation, the structural details of them and their functions (negative/positive) in multiple disease models in both animal models and human. The wide range of the stimuli makes the function of inflammasome diverse and complex. Here, we review the structure, biological functions, and therapeutic targets of inflammasomes, while highlight NLRP3, NLRC4, and AIM2 inflammasomes, which are the most well studied. In conclusion, this review focuses on the activation process, biological functions, and structure of the most well‐studied inflammasomes, summarizing and predicting approaches for disease treatment and prevention with inflammasome as a target. We aim to provide fresh insight into new solutions to the challenges in this field.

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An all-in-one adjuvanted therapeutic cancer vaccine targeting dendritic cell cytosol induces long-lived tumor suppression through NLRC4 inflammasome activation

Cited by 14 publications

References 57 publications

mRNA‐HPV vaccine encoding E6 and E7 improves therapeutic potential for HPV‐mediated cancers via subcutaneous immunization

mRNA‐HPV vaccine encoding E6 and E7 improves therapeutic potential for HPV‐mediated cancers via subcutaneous immunization

Studies on the structure and stimulating effect on Caco-2 cells of flagellin and its truncated proteins of Escherichia coli Nissle 1917

Inflammasome: structure, biological functions, and therapeutic targets

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