Harnessing human immune system models to validate NADPH oxidase 1 inhibition as treatment for hepatocellular carcinoma
Frontiers in Pharmacology, cilt.17, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 17
- Basım Tarihi: 2026
- Doi Numarası: 10.3389/fphar.2026.1808515
- Dergi Adı: Frontiers in Pharmacology
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, EMBASE, Directory of Open Access Journals, Natural Science Collection (ProQuest), Biological Science Database (ProQuest)
- Anahtar Kelimeler: adaptive immunity, cancer immunity, hepatocellular carcinoma, human immune system mouse models, humanized models, innate immunity, NADPH oxidase 1, precision-cut tumor slices
- Sağlık Bilimleri Üniversitesi Adresli: Evet
Özet
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 ex vivo patient-derived precision-cut tumor slices (PCTS). 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 VCAM1 and ICAM1 expression. NOX1i-treated Myeloid-HIS-HCC mice showed a similar shift in tumor-promoting cytokines and immune checkpoints as NOX1i-treated T cell-HIS-HCC mice. Moreover, gene expression of tumor-associated macrophage, HCC and proliferation markers tended to be lower in tumors of NOX1i-treated Myeloid-HIS-HCC mice. Ex vivo patient-derived PCTS treated with NOX1i also demonstrated lower gene expression of pro-tumorigenic cytokines and tumor-promoting markers. 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.