Immune modulation of liver sinusoidal endothelial cells by melittin nanoparticles suppresses liver metastasis

Yu, Xiao; Chen, Lu; Liu, Jianqiao; Dai, Bolei; Xu, Guoqiang; Shen, Guanxin; Luo, Qingming; Zhang, Zhihong

doi:10.1038/s41467-019-08538-x

Cited by 93 publications

(76 citation statements)

References 47 publications

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“…In addition, we found that α-melittin-NPs could induce the maturation of macrophages and DCs in LNs and cause dramatic changes in the cytokine/ chemokine milieu in the tumor. These results were consistent with our recently published study about the immunomodulatory effects of α-melittin-NPs on LSECs 37 . We also noticed that the cytokine/ chemokine secretion profiles were not uniform, probably because of the existence of strong intrinsic immune suppression environment in liver.…”

Section: Discussionsupporting

confidence: 94%

Melittin-lipid nanoparticles target to lymph nodes and elicit a systemic anti-tumor immune response

et al. 2020

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Targeted delivery of a nanovaccine loaded with a tumor antigen and adjuvant to the lymph nodes (LNs) is an attractive approach for improving cancer immunotherapy outcomes. However, the application of this technique is restricted by the paucity of suitable tumorassociated antigens (TAAs) and the sophisticated technology required to identify tumor neoantigens. Here, we demonstrate that a self-assembling melittin-lipid nanoparticle (α-melittin-NP) that is not loaded with extra tumor antigens promotes whole tumor antigen release in situ and results in the activation of antigen-presenting cells (APCs) in LNs. Compared with free melittin, α-melittin-NPs markedly enhance LN accumulation and activation of APCs, leading to a 3.6-fold increase in antigen-specific CD8 + T cell responses. Furthermore, in a bilateral flank B16F10 tumor model, primary and distant tumor growth are significantly inhibited by α-melittin-NPs, with an inhibition rate of 95% and 92%, respectively. Thus, α-melittin-NPs induce a systemic anti-tumor response serving as an effective LN-targeted whole-cell nanovaccine.

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Section: Discussionsupporting

confidence: 94%

Melittin-lipid nanoparticles target to lymph nodes and elicit a systemic anti-tumor immune response

et al. 2020

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“…For example, nanoparticles developed to interact exclusively with LSEC have been trialled in murine models of liver metastasis. Yu and colleagues reported that LSEC are specifically targeted by alpha-melittin nanoparticles ( Yu et al, 2019 ), which increase numbers of innate and adaptive immune cells in addition to promoting T cell activation and NK cell maturation. Their ability to prime the anti-tumour response prevents the formation of metastasis.…”

Section: Targeting Lsec In Inflammation and Cancer Therapymentioning

confidence: 99%

“…Moreover, melittin nanoparticles have a direct cytotoxic effect on metastatic tumours. Mice treated with melittin nanoparticles had significantly improved survival rates ( Yu et al, 2019 ). Using miRNA conjugated with chondroitin sulfate-functionalised nanoparticles, Marquez and colleagues targeted LSEC activation during angiogenesis.…”

Section: Targeting Lsec In Inflammation and Cancer Therapymentioning

confidence: 99%

The Role of Sinusoidal Endothelial Cells in the Axis of Inflammation and Cancer Within the Liver

2020

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Liver sinusoidal endothelial cells (LSEC) form a unique barrier between the liver sinusoids and the underlying parenchyma, and thus play a crucial role in maintaining metabolic and immune homeostasis, as well as actively contributing to disease pathophysiology. Whilst their endocytic and scavenging function is integral for nutrient exchange and clearance of waste products, their capillarisation and dysfunction precedes fibrogenesis. Furthermore, their ability to promote immune tolerance and recruit distinct immunosuppressive leukocyte subsets can allow persistence of chronic viral infections and facilitate tumour development. In this review, we present the immunological and barrier functions of LSEC, along with their role in orchestrating fibrotic processes which precede tumourigenesis. We also summarise the role of LSEC in modulating the tumour microenvironment, and promoting development of a pre-metastatic niche, which can drive formation of secondary liver tumours. Finally, we summarise closely inter-linked disease pathways which collectively perpetuate pathogenesis, highlighting LSEC as novel targets for therapeutic intervention.

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“…This ligand has been used to increase LSEC delivery by coating liposomes [266], lipid particles [267] and quantum dots [268]. Apolipoprotein B, or a part of its sequence, that is also a ligand for scavenger receptors stabilin-1 and 2 has been used to decorate nanoparticles [269,270] and liposomes [271]. Furthermore, the polymer poly(maleic anhydride-alt-1-octadecene) has also been used to coat superparamagnetic iron oxide nanoparticles in order to direct them to the sinusoidal endothelium [272].…”

Section: Lsec Targeting: Potential For Therapymentioning

confidence: 99%

“…For the moment, LSEC targeting strategies have been employed in the context of cancer, autoimmunity, acute liver damage, ischemia-reperfusion injury and haemophilia [5,262,264,270,272,276], but they represent an attractive treatment also for liver fibrosis.…”

Section: Lsec Targeting: Potential For Therapymentioning

confidence: 99%

The Endothelium as a Driver of Liver Fibrosis and Regeneration

Lafoz

Ruart

Anton

et al. 2020

Cells

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Liver fibrosis is a common feature of sustained liver injury and represents a major public health problem worldwide. Fibrosis is an active research field and discoveries in the last years have contributed to the development of new antifibrotic drugs, although none of them have been approved yet. Liver sinusoidal endothelial cells (LSEC) are highly specialized endothelial cells localized at the interface between the blood and other liver cell types. They lack a basement membrane and display open channels (fenestrae), making them exceptionally permeable. LSEC are the first cells affected by any kind of liver injury orchestrating the liver response to damage. LSEC govern the regenerative process initiation, but aberrant LSEC activation in chronic liver injury induces fibrosis. LSEC are also main players in fibrosis resolution. They maintain liver homeostasis and keep hepatic stellate cell and Kupffer cell quiescence. After sustained hepatic injury, they lose their phenotype and protective properties, promoting angiogenesis and vasoconstriction and contributing to inflammation and fibrosis. Therefore, improving LSEC phenotype is a promising strategy to prevent liver injury progression and complications. This review focuses on changes occurring in LSEC after liver injury and their consequences on fibrosis progression, liver regeneration, and resolution. Finally, a synopsis of the available strategies for LSEC-specific targeting is provided.

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Immune modulation of liver sinusoidal endothelial cells by melittin nanoparticles suppresses liver metastasis

Cited by 93 publications

References 47 publications

Melittin-lipid nanoparticles target to lymph nodes and elicit a systemic anti-tumor immune response

Melittin-lipid nanoparticles target to lymph nodes and elicit a systemic anti-tumor immune response

The Role of Sinusoidal Endothelial Cells in the Axis of Inflammation and Cancer Within the Liver

The Endothelium as a Driver of Liver Fibrosis and Regeneration

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