Dihydroartemisinin increased the abundance of Akkermansia muciniphila by YAP1 depression that sensitizes hepatocellular carcinoma to anti-PD-1 immunotherapy

Abstract

The effect of anti-programmed cell death 1 (anti-PD-1) immunotherapy is limited in patients with hepatocellular carcinoma (HCC). Yes-associated protein 1 (YAP1) expression increased in liver tumor cells in early HCC, and Akkermansia muciniphila abundance decreased in the colon. The response to anti-PD-1 treatment is associated with A. muciniphila abundance in many tumors. However, the interaction between A. muciniphila abundance and YAP1 expression remains unclear in HCC. Here, anti-PD-1 treatment decreased A. muciniphila abundance in the colon, but increased YAP1 expression in the tumor cells by mice with liver tumors in situ. Mechanistically, hepatocyte-specific Yap1 knockout (Yap1^LKO) maintained bile acid homeostasis in the liver, resulting in an increased abundance of A. muciniphila in the colon. Yap1 knockout enhanced anti-PD-1 efficacy. Therefore, YAP1 inhibition is a potential target for increasing A. muciniphila abundance to promote anti-PD-1 efficacy in liver tumors. Dihydroartemisinin (DHA), acting as YAP1 inhibitor, increased A. muciniphila abundance to sensitize anti-PD-1 therapy. A. muciniphila by gavage increased the number and activation of CD8⁺ T cells in liver tumor niches during DHA treatment or combination with anti-PD-1. Our findings suggested that the combination anti-PD-1 with DHA is an effective strategy for liver tumor treatment.

Keywords

hepatocellular carcinoma / YAP1 / Akkermansia muciniphila / anti-PD-1 / dihydroartemisinin / bile acid

Zhiqin Zhang et al.

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Acknowledgements

We would like to thank the National Natural Science Foundation of China (No. 81873112) and Science and Technology Project of Hebei Education Department (No. ZD2022120) for the economic support.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-022-0978-2 and is accessible for authorized users.

Compliance with ethics guidelines

Zhiqin Zhang, Xinli Shi, Jingmin Ji, Yinglin Guo, Qing Peng, Liyuan Hao, Yu Xue, Yiwei Liu, Caige Li, Junlan Lu, and Kun Yu declare that they have no conflict of interest. All institutional and national guidelines for the care and use of laboratory animals were followed.

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