Relaxin gene delivery mitigates liver metastasis and synergizes with check point therapy

Mengying Hu, Ying Wang, Ligeng Xu, Sai An, Yu Tang, Xuefei Zhou, Jingjing Li, Rihe Liu and Leaf Huang ()
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Mengying Hu: University of North Carolina
Ying Wang: University of North Carolina
Ligeng Xu: University of North Carolina
Sai An: University of North Carolina
Yu Tang: University of North Carolina
Xuefei Zhou: University of North Carolina
Jingjing Li: University of North Carolina
Rihe Liu: University of North Carolina
Leaf Huang: University of North Carolina

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract Activated hepatic stellate cell (aHSC)-mediated liver fibrosis is essential to the development of liver metastasis. Here, we discover intra-hepatic scale-up of relaxin (RLN, an anti-fibrotic peptide) in response to fibrosis along with the upregulation of its primary receptor (RXFP1) on aHSCs. The elevated expression of RLN serves as a natural regulator to deactivate aHSCs and resolve liver fibrosis. Therefore, we hypothesize this endogenous liver fibrosis repair mechanism can be leveraged for liver metastasis treatment via enforced RLN expression. To validate the therapeutic potential, we utilize aminoethyl anisamide-conjugated lipid-calcium-phosphate nanoparticles to deliver plasmid DNA encoding RLN. The nanoparticles preferentially target metastatic tumor cells and aHSCs within the metastatic lesion and convert them as an in situ RLN depot. Expressed RLN reverses the stromal microenvironment, which makes it unfavorable for established liver metastasis to grow. In colorectal, pancreatic, and breast cancer liver metastasis models, we confirm the RLN gene therapy results in significant inhibition of metastatic progression and prolongs survival. In addition, enforced RLN expression reactivates intra-metastasis immune milieu. The combination of the RLN gene therapy with PD-L1 blockade immunotherapy further produces a synergistic anti-metastatic efficacy. Collectively, the targeted RLN gene therapy represents a highly efficient, safe, and versatile anti-metastatic modality, and is promising for clinical translation.

Date: 2019
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DOI: 10.1038/s41467-019-10893-8

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