Vx3-Functionalized Alumina Nanoparticles Assisted Enrichment of Ubiquitinated Proteins from Cancer Cells for Enhanced Cancer Immunotherapy

Zhao, Jinjin; Pan, Ning; Huang, Fang; Aldarouish, Mohanad; Zhang, Wen; Gao, Rong; Zhang, Yuanjian; Hu, Hong-Ming; Shen, Yanfei; Wang, Li-xin

doi:10.1021/acs.bioconjchem.7b00578

Cited by 14 publications

(20 citation statements)

References 54 publications

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“…As mentioned previously, the success of peptide-based vaccines mainly depends on the utilized peptides and selection of an appropriate adjuvant. Herein, it has been found that the covalent linking of adjuvant to tumor-associated antigens (TAAs) could result in the maturation and activation of DCs in vitro and induced a potent antitumor immune response in vivo compared to TAAs which they physically mixed with adjuvant [30,31].…”

Section: Discussionmentioning

confidence: 99%

Triggered Immune Response Induced by Antigenic Epitopes Covalently Linked with Immunoadjuvant-Pulsed Dendritic Cells as a Promising Cancer Vaccine

Chen

Aldarouish

et al. 2020

Journal of Immunology Research

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The success of peptide-based dendritic cell (DC) cancer vaccines mainly depends on the utilized peptides and selection of an appropriate adjuvant. Herein, we aimed to evoke a broad immune response against multiple epitopes concurrently in the presence of immunoadjuvant. Three synthetic HLA-A∗0201-restricted peptides were separately linked with HMGB1-derived peptide (SAFFLFCSE, denoted as HB100-108) as immunoadjuvant via double arginine (RR) linker and loaded onto human monocyte-derived DCs. Peptide uptake was detected by immunofluorescence microscopy and flow cytometry. The maturation and activation status of pulsed DCs were monitored by detection of the expression of specific markers and released cytokines. The ability of peptide-pulsed DCs to activate allogeneic T cells has been assessed by a degranulation assay and detection of secreted cytokines. The lytic activity of effector T cells against cancer cells in vitro was analyzed by a lactate dehydrogenase (LDH) assay. Results revealed that DCs efficiently take up peptides+HB100-108 and expressed higher levels of surface markers (HLA-ABC, HLA-DR, CD80, CD86, CD83, CD40, and CCR7) and proinflammatory cytokines (IL-6, IFN-γ, TNF-α, and IL-12) than control DCs, free peptide-pulsed DCs, and free HB100-108-pulsed DC groups. Moreover, peptides+HB100-108/pulsed DCs were capable of activating allogeneic T cells and enhance their lytic activity against a pancreatic cancer cell line (PANC-1) in vitro. These findings suggest that antigenic peptides covalently linked with HB100-108/pulsed DCs could be a promising strategy to improve the current DC-based cancer vaccines.

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Section: Discussionmentioning

confidence: 99%

Triggered Immune Response Induced by Antigenic Epitopes Covalently Linked with Immunoadjuvant-Pulsed Dendritic Cells as a Promising Cancer Vaccine

Chen

Aldarouish

et al. 2020

Journal of Immunology Research

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“…These nanoparticles are ubiquitinated, allowing them to bind with selective autophagy receptor proteins, such as SQSTM1, and are then linked to an LC3-interacting region, resulting in autophagic machinery and degradation in lysosomes. [30][31][32] Several studies have reported the ubiquitination or Ub-decorated nanoparticles either directly [34,101,118,[178][179][180][181][182][183][184][185][186][187][188][189][190] or indirectly [191][192][193][194] for processing through the selective autophagy pathway ( Table 3). These nanoparticles may be delivered through the Ub-decorated mechanisms to mediate binding to autophagy receptors for entry into selective autophagy pathways.…”

Section: Interaction Of Ubiquitin and Nanoparticlesmentioning

confidence: 99%

“…Nanoparticles or nanodrugs may be decorated with Ub through different mechanisms. Previous studies have reported that nanoparticles were either directly [34,101,118,178,180] or indirectly [34,192,194] binding to Ub proteins. Thereafter, nanoparticles and nanodrugs attach to cargo to become engulfed by the phagophores through binding to ubiquitinated cargos, selective autophagy receptors, and LC3 regions, to form a double-membrane-vesicle nanoparticulosomes (Figure 5c,d).…”

Section: Three Possible Pathways Of Nanoparticulophagymentioning

confidence: 99%

Selective Autophagy Pathway of Nanoparticles and Nanodrugs: Drug Delivery and Pathophysiological Effects

Raj

Lin

Chen

et al. 2020

Advanced Therapeutics

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Research attention has been given to selective autophagy due to its potential application in the pathophysiology of human diseases. The selective autophagy pathway contributes to the target recognition and degradation of intracellular components or foreign pathogens for maintaining cellular homeostasis in multiple organisms. Notably, this process is mediated by autophagy receptors in the recognition of autophagy cargoes through binding to the ubiquitin‐binding domain and LC3‐interacting region to the formation of autophagosomes. Nanotechnology is an emerging field; related research has focused on the study and manipulation of nanoscale materials that can be applied for numerous applications, especially for the diagnosis and treatment of human diseases. Nanoparticle‐mediated autophagy activation holds promise for use in autophagy‐related disease applications. The selective autophagy of nanoparticles and nanodrugs occurs through binding to ubiquitinated proteins, autophagy receptors, and LC3, the formation of nanoparticulosomes, and their delivery to lysosomes; the process is termed nanoparticulophagy. This review focuses on the mechanisms of nanoparticulophagy, the role of selective autophagy receptors, and potential applications in autophagy‐related diseases achieved using these nanoparticles and nanodrugs. Nanoparticulophagy will provide an understanding of related intracellular trafficking mechanisms and degradation pathways for processing nanoparticles and nanodrugs in terms of drug delivery and pathophysiological effects.

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“…Therefore, different strategies for UPs enrichment have been developed to achieve a clinically safe, simply made, and environment-friendly vaccine with enhanced antitumor immune response. [19][20][21] In our previous studies, we enriched UPs from tumor cells after proteasome inhibition by Ni-NTA agarose beads conjugated with ubiquitin-binding protein Vx3. We found that the UPs have the ability to be an effective cancer vaccine.…”

Section: Introductionmentioning

confidence: 99%

<p>Anti-Tumor Efficacy of an Adjuvant Built-In Nanovaccine Based on Ubiquitinated Proteins from Tumor Cells</p>

Huang¹,

Zhao²,

Wei³

et al. 2020

IJN

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Background and Aim: We have previously identified ubiquitinated proteins (UPs) from tumor cell lysates as a promising vaccine for cancer immunotherapy in different mouse tumor models. In this study, we aimed at developing a highly efficient therapeutic adjuvant built-in nanovaccine (α-Al 2 O 3-UPs) by a simple method, in which UPs from tumor cells could be efficiently and conveniently enriched by α-Al 2 O 3 nanoparticles covalently coupled with Vx3 proteins (α-Al 2 O 3-CONH-Vx3). Methods: The α-Al 2 O 3 nanoparticles were modified with 4-hydroxybenzoic acid followed by coupling with ubiquitin-binding protein Vx3. It was then used to enrich UPs from 4T1 cell lysate. The stability and the efficiency for the UPs enrichment of α-Al 2 O 3-CONH-Vx3 were examined. The ability of α-Al 2 O 3-UPs to activate DCs was examined in vitro subsequently. The splenocytes from the vaccinated mice were re-stimulated with inactivated tumor cells, and the IFN-γ secretion was detected by ELISA and flow cytometry. Moreover, the therapeutic efficacy of α-Al 2 O 3-UPs, alone and in combination with chemotherapy, was examined in 4T1 tumor-bearing mice. Results: Our results showed that α-Al 2 O 3-UPs were successfully synthesized and abundant UPs from tumor cell lysate were enriched by the new method. In vitro study showed that compared to the physical mixture of α-Al 2 O 3 nanoparticles and UPs (α-Al 2 O 3 +UPs), α-Al 2 O 3-UPs stimulation resulted in higher upregulations of CD80, CD86, MHC class I, and MHC class II on DCs, indicating the higher ability of DC activation. Moreover, α-Al 2 O 3-UPs elicited a more effective immune response in mice, demonstrated by higher IFN-γ secretion than α-Al 2 O 3 +UPs. Furthermore, α-Al 2 O 3-UPs also exhibited a more potent effect on tumor growth inhibition and survival prolongation in 4T1 tumor-bearing mice. Notably, when in combination with low dose chemotherapy, the anti-tumor effect was further enhanced, rather than using α-Al 2 O 3-UPs alone. Conclusion: This study presents an adjuvant built-in nanovaccine generated by a new simple method that can be potentially applied to cancer immunotherapy and lays the experimental foundation for future clinical application.

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Vx3-Functionalized Alumina Nanoparticles Assisted Enrichment of Ubiquitinated Proteins from Cancer Cells for Enhanced Cancer Immunotherapy

Cited by 14 publications

References 54 publications

Triggered Immune Response Induced by Antigenic Epitopes Covalently Linked with Immunoadjuvant-Pulsed Dendritic Cells as a Promising Cancer Vaccine

Triggered Immune Response Induced by Antigenic Epitopes Covalently Linked with Immunoadjuvant-Pulsed Dendritic Cells as a Promising Cancer Vaccine

Selective Autophagy Pathway of Nanoparticles and Nanodrugs: Drug Delivery and Pathophysiological Effects

<p>Anti-Tumor Efficacy of an Adjuvant Built-In Nanovaccine Based on Ubiquitinated Proteins from Tumor Cells</p>

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