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

• Published in: Molecular oncology Vol. 14; no. 11; pp. 2920 - 2935
• Main Authors: Xia, Yujia, He, Jiayi, Zhang, Hongji, Wang, Han, Tetz, George, Maguire, Casey A., Wang, Yu, Onuma, Amblessed, Genkin, Dmitry, Tetz, Victor, Stepanov, Alexey, Terekhov, Stanislav, Ukrainskaya, Valeria, Huang, Hai, Tsung, Allan
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-11-2020; John Wiley and Sons Inc; Wiley
• Subjects: Actin; Adaptive immunity; Adenocarcinoma; adeno‐associated virus; Animal models; Apolipoprotein E; Bevacizumab; Cancer; Cancer therapies; Chemotherapy; Colorectal cancer; Colorectal carcinoma; Deoxyribonuclease; Deoxyribonuclease I; Deoxyribonucleic acid; DNA; Drug dosages; Drug resistance; Gene therapy; Gene transfer; Genes; Genetic aspects; Health aspects; Hepatitis; Immune response; Inflammation; Innate immunity; Liver; Liver cancer; Metastases; Metastasis; metastatic colorectal cancer; Monoclonal antibodies; neutrophil extracellular traps; Neutrophils; Nucleases; Post-transcription; Proteins; Scientific equipment and supplies industry; T cells; Targeted cancer therapy; Veins & arteries; United States; California; United States > US; China; metastatic colorectal cancer; adeno-associated virus; Deoxyribonuclease I; neutrophil extracellular traps
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12787

Liver metastasis is a major cause of colorectal cancer‐related death. Although DNase I displays antimetastatic activity by inhibition of NETs, its clinical use is limited due to its short biologic half‐life. AAV‐mediated gene expression of DNase I is a novel therapeutic strategy that could reduce the development of liver metastases through modulation of innate and adaptive tumor immunity.
Liver metastasis is the main cause of colorectal cancer (CRC)‐related death. Neutrophil extracellular traps (NETs) play important roles in CRC 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 antimetastatic 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 CRC liver metastasis. Increased levels of neutrophils and NET formation in tumors are 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 while 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 CRC.