Liver cancer is the third leading cause of cancerassociated mortality worldwide. By the time liver cancer is diagnosed, it is already in the advanced stage. Therefore, novel therapeutic strategies need to be identified to improve the prognosis of patients with liver cancer. In the present study, the profiles of GSE84402, GSE19665 and GSE121248 were used to screen differentially expressed genes (DEGs).
The efficacy of anti‐PD‐1 therapy is not as expected in hepatocellular carcinoma (HCC). YAP1 was overexpressed and activated in HCC. The mechanism of YAP1 in HCC immune escape is unclear. Anti‐PD‐1 treatment increased YAP1 expression in liver tumor cells, and exhausted CD4+ and CD8+ T cells in the blood and spleen of liver tumor mice. YAP1 knockdown suppressed PD‐L1 expression, which was involved in JAK1/STAT1, 3 pathways. Moreover, Yap1 knockout elevated CD4+ and CD8+ T cells in liver tumor niche. Consistently, verteporfin, YAP1 inhibitor, decreased TGF‐β and IFN‐γ in liver tumor niche and exhausted CD8+ T cell in the spleen. DHA suppressed YAP1 expression and break immune evasion in liver tumor niche, characterized by decreased PD‐L1 in liver tumor cells and increased CD8+ T cell infiltration. Furthermore, DHA combined with anti‐PD‐1 treatment promoted CD4+ T cell infiltration in the spleen and CD8+ T cell in tumor tissues of mice. In summary, YAP1 knockdown in liver tumor cells suppressed PD‐L1 expression and recruited cytotoxic T lymphocytes (CTLs), leading to break immune evasion in tumor niche. Mechanistically, YAP1 knockdown suppressed PD‐L1 expression, which was involved in JAK1/STAT1, 3 pathways. Finally, DHA inhibited YAP1 expression, which not only inhibited liver tumor proliferation but also break the immunosuppressive niche in liver tumor tissues and improve the effect of anti‐PD‐1 therapy.
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