Liver-directed AAV-IL-10 therapy enhances CD8T cell-mediated immunity against hepatocellular carcinoma.

Abstract

BACKGROUND: The liver's inherently immunosuppressive microenvironment presents a major barrier to effective immunotherapy for hepatocellular carcinoma (HCC). Although interleukin-10 (IL-10) has demonstrated antitumor activity in several cancer models, its therapeutic potential in HCC remains unclear. Here, we investigated whether liver-directed delivery of IL-10 using an adeno-associated virus vector (AAV-IL-10) could enhance antitumor immunity in HCC. METHODS: Syngeneic orthotopic and intrahepatic metastatic HCC mouse models were used to evaluate the effects of liver-directed AAV-IL-10 therapy. Tumor burden, immune cell infiltration, and functional activation were assessed by flow cytometry and related analyses. RESULTS: Liver-directed AAV-IL-10 treatment significantly reduced intrahepatic tumor burden and promoted robust infiltration of CD8T cells into the tumor microenvironment. AAV-IL-10 enhanced the functional activation of natural killer cells and CD8T cells, as reflected by increased expression of effector cytokines and cytotoxic molecules. Notably, AAV-IL-10 augmented the effector capacity of terminally exhausted CD8tumor-infiltrating lymphocytes and expanded a population of CD8T cells with a tissue-resident memory (Trm)-like phenotype. These Trm-like CD8T cells were liver-resident and persisted after tumor clearance. Importantly, the antitumor effects of AAV-IL-10 were confined to the liver and did not affect the growth of distant subcutaneous tumors. CONCLUSIONS: Liver-directed AAV-IL-10 delivery overcomes local immunosuppression and enhances CD8T cell-mediated antitumor immunity in murine HCC models. These findings support targeted IL-10 delivery as a promising strategy to improve immunotherapy outcomes in liver cancer.