Harnessing human immune system models to validate NADPH oxidase 1 inhibition as treatment for hepatocellular carcinoma.

Introduction: NADPH oxidase 1 inhibition (NOX1i) has shown to alter the tumor microenvironment in conventional mouse models for hepatocellular carcinoma (HCC). However, clinical translation is hampered by low translatability of these models. Methods: We developed two novel human immune system (HIS) mouse models, co-transplanted with orthotopic human HCC cells, to investigate NOX1i in the context of human HCC and human adaptive (T cell-HIS-HCC) or innate (Myeloid-HIS-HCC) immune responses. Mice received NOX1i or vehicle twice per week for 3 weeks. Results were validated in Results: T cell-HIS-HCC mice were mainly reconstituted with human T cells. Interestingly, the expression of cytokines and markers involved in both cancer progression and anti-tumor immunity was significantly lower in tumors of NOX1i-treated mice. In the Myeloid-HIS-HCC model, humanization in livers and tumors was dominated by macrophages. Significantly lower human immune cells were observed in tumors of NOX1i-treated Myeloid-HIS-HCC mice, in line with reduced Conclusion: Our data show that NOX1i modulates the tumor-immune microenvironment in human immune system HCC models, and might hold potential in combination therapy to rebalance the dysregulated immune profile in HCC.