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

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

doi:10.1038/s41467-019-08538-x

Abstract

Liver sinusoidal endothelial cells (LSECs) are responsible for the immunologic tolerance of liver which is a common site for visceral metastases, suggesting its potential role as an target for cancer immunotherapy. However, targeted modulation of LSECs is still not achieved thus far. Here, we report LSECs are specifically targeted and modulated by melittin nanoparticles (α-melittin-NPs). Intravital imaging shows that LSECs fluoresce within 20 s after intravenous injection of α-melittin-NPs. α-melittin-NPs trigger the activation of LSECs and lead to dramatic changes of cytokine/chemokine milieu in the liver, which switches the hepatic immunologic environment to the activated state. As a result, α-melittin-NPs resist the formation of metastatic lesions with high efficiency. More strikingly, the survival rate reaches 80% in the spontaneous liver metastatic tumor model. Our research provides support for the use of α-melittin-NPs to break LSEC-mediated immunologic tolerance, which opens an avenue to control liver metastasis through the immunomodulation of LSECs.

Highlights

Liver sinusoidal endothelial cells (LSECs) are responsible for the immunologic tolerance of liver which is a common site for visceral metastases, suggesting its potential role as an target for cancer immunotherapy
To further confirm that the strip-like distribution of α-melittin-NPs in the hepatic sinusoid was attributable to its specific targeting of LSECs, we used multicolor flow cytometry to analyze the uptake of α-melittin-NP by the nonparenchymal cells in the liver, such as LSECs, Kupffer cells (KCs), dendritic cell (DC), monocyte-derived macrophages (MoMFs), and neutrophils
We demonstrate the ability of α-melittin-NP to reverse the tolerogenic liver environment by targeting and regulating the LSECs, resisting the development of liver metastasis from different tumor models

Summary

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Taken together, these findings demonstrate that α-melittin-NPs stimulate the differentiation and maturation of NK cells, and trigger T-cellmediated systemic anti-tumor immune responses in the livers of tumor-bearing mice. Effect of α-melittin-NPs on the spontaneous liver metastasis. Though the experimental metastasis model is highly reproducible and saves time when developing liver metastases, it hardly represents the natural metastatic process that involves tumor cell local invasion and extravasation into distant organs[33].

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