D2.442 - AAV-Mediated IL-10 Gene Delivery Enhances Antitumor Immunity While Preserving Immune Tolerance in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality, and although immunotherapies can elicit potent antitumor responses, excessive or dysregulated immune activation may result in immune-related adverse events resembling hypersensitivity or inflammatory pathology. Interleukin-10 (IL-10) is a key immunoregulatory cytokine capable of limiting tissue-damaging inflammation while maintaining effective cytotoxic immunity; however, its therapeutic application is limited by a short in vivo half-life. To evaluate both antitumor efficacy and immune safety, we employed an adeno-associated virus (AAV) vector to achieve sustained hepatic delivery of IL-10 in an orthotopic HCC mouse model.

Hep55.1c hepatoma cells were inoculated into the left liver lobe of C57BL/6 mice, followed by intravenous administration of AAV encoding IL-10 (AAV-IL-10) or control vector.

AAV-IL-10 induced sustained IL-10 expression, significantly reduced tumor burden, and prolonged survival after tumor implantation. Immune profiling revealed increased tumor-infiltrating leukocytes, particularly CD8⁺ T cells, with enhanced interferon-γ and granzyme B production in both CD8⁺ T cells and natural killer cells. Importantly, despite augmented cytotoxic immunity, AAV-IL-10 did not induce hepatotoxicity, as indicated by normal serum alanine and aspartate aminotransferase levels. Although mild immune cell infiltration was observed in selected peripheral organs, no histological evidence of tissue injury or functional impairment was detected.

These findings demonstrate that sustained hepatic IL-10 gene delivery can promote effective antitumor immunity while preserving immune tolerance, supporting its potential as a safe immunomodulatory strategy for liver cancer therapy.