AAV-mediated gene transfer of DNase I in the liver of mice with colorectal cancer reduces liver metastasis and restores local innate and adaptive immune response

Colorectal Cancer
20/08/2020

Mol Oncol. 2020 Aug 19. doi: 10.1002/1878-0261.12787. Online ahead of print.

ABSTRACT

Liver metastasis is the main cause of colorectal cancer-related death. Neutrophil extracellular traps (NETs) play important roles in colorectal cancer progression. Deoxyribonuclease I (DNase I) has been shown to alter NET function by cleaving DNA strands comprising the NET backbone. Moreover, DNase I displays high anti-metastatic activity in multiple tumor models. To circumvent long term daily administrations of recombinant DNase I, we have developed an adeno-associated virus (AAV) gene therapy


vector to specifically express DNase I in the liver. In this study, we demonstrate AAV-mediated DNase I liver gene transfer following a single intravenous injection suppresses the development of liver metastases in a mouse model of colorectal cancer liver metastasis. Increased levels of neutrophils and NET formation in tumors is associated with poor prognosis in many patients with advanced cancers. Neutrophil infiltration and NET formation were inhibited in tumor tissues with AAV-DNase I treatment. This approach restored local immune responses at the tumor site by increasing the percentage of CD8+ T cells whilst keeping CD4+ T cells similar between AAV-DNase I and AAV-null treatments. Our data suggest that AAV mediated DNase I liver gene transfer is a safe and effective modality to inhibit metastasis and represents a novel therapeutic strategy for colorectal cancer.