Dihydroartemisinin broke the tumor immunosuppressive microenvironment by inhibiting YAP1 expression to enhance anti‐PD‐1 efficacy

• Published in: Phytotherapy research Vol. 37; no. 5; pp. 1740 - 1753
• Main Authors: Peng, Qing, Li, Shenghao, Shi, Xinli, Guo, Yinglin, Hao, Liyuan, Zhang, Zhiqin, Ji, Jingmin, Zhao, Yanmeng, Li, Caige, Xue, Yu, Liu, Yiwei
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.05.2023; Wiley Subscription Services, Inc
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animal tissues; Animals; B7-H1 Antigen; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes; Cytotoxicity; Dihydroartemisinin; Effectiveness; Hepatocellular carcinoma; Hepatocytes; immune microenvironment; Immunosuppressive Agents; Infiltration; Janus kinase; Liver; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Lymphocytes; Lymphocytes T; Metastases; Mice; Microenvironments; PD-L1 protein; PD‐L1; Spleen; Stat1 protein; Transcription Factors - metabolism; Tumor cells; Tumor Microenvironment; Tumors; YAP1; Yes-associated protein; Dihydroartemisinin; YAP1; PD-L1; immune microenvironment; hepatocellular carcinoma
• ISSN: 0951-418X; 1099-1573
• DOI: 10.1002/ptr.7695

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.