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

doi:10.1007/s11684-022-0978-2

Front. Med.

2023, Vol. 17

Issue (4) : 729-746 https://doi.org/10.1007/s11684-022-0978-2

RESEARCH ARTICLE

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

Zhiqin Zhang, Xinli Shi(

), Jingmin Ji, Yinglin Guo, Qing Peng, Liyuan Hao, Yu Xue, Yiwei Liu, Caige Li, Junlan Lu, Kun Yu

Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang 050200, China

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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

Corresponding Author(s): Xinli Shi

Just Accepted Date: 21 March 2023 Online First Date: 28 April 2023 Issue Date: 12 October 2023

Cite this article:

Zhiqin Zhang,Xinli Shi,Jingmin Ji, et al. Dihydroartemisinin increased the abundance of Akkermansia muciniphila by YAP1 depression that sensitizes hepatocellular carcinoma to anti-PD-1 immunotherapy[J]. Front. Med., 2023, 17(4): 729-746.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-022-0978-2
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I4/729

Fig.1 DHA increased the abundance of A. muciniphila during anti-PD-1 treatment in C57BL/6 mice with liver tumors. (A) Schematic of liver tumor in situ model in C57BL/6 mice induced by DEN/TCPOBOP and treated with DHA, anti-PD-1 or DHA + anti-PD-1. (B, C) Number and maximal size of liver tumors in each group. Data are represented as mean ± SD (n = 5 per group), *P < 0.05. (D) Common and unique OTUs between different groups by Venn diagram. (E) Annotation and content of the top 20 species in abundance at the genus level by heatmap. (F) Histogram of relative abundance of the top 10 species.

Fig.2 A. muciniphila was enriched in the DHA + anti-PD-1 group in C57BL/6 mice with heterotopic tumors. (A) Schematic of heterotopic tumor model in C57BL/6 mice induced by Hepa1-6 cells and treated with DHA, anti-PD-1 or DHA + anti-PD-1. (B) OTUs from DMSO, DHA, anti-PD-1, and DHA + anti-PD-1 groups by Venn diagram. (C) Species annotation and the top 20 abundance information from each group at the genus level by heatmap. (D) Principal coordinate analysis of bacterial community differences (n = 4 per group). (E) Histogram of linear discriminant analysis (LDA) between DMSO, DHA, anti-PD-1, and DHA + anti-PD-1 groups.

Fig.3 A. muciniphila ameliorated the tumor immunosuppressive microenvironment in the combination of anti-PD-1 and DHA treatment. (A) The heterotopic tumor model was induced by Hepa1-6 cells in the decreased abundance of A. muciniphila mice treated with ATB. The mice were treated with the combination of DHA and anti-PD-1, and A. muciniphila or sterile water was administered by oral gavage after stopping the ATB treatment. (B) Plate culture of A. muciniphila from mice in ATB and sterile water groups. (C and D) Representative liver tumor pictures, weight and volume of tumors in sterile water + DHA + anti-PD-1 and A. muciniphila + DHA + anti-PD-1 groups. Data are represented as mean ± SD (n = 5 per group), *P < 0.05. (E and F) Representative pictures and quantification of CD8⁺ T in CD3⁺ T cells in blood and spleen by flow cytometry analysis. ns, no significance. (G) Representative pictures of H&E and immunohistochemical staining of CD8 from tumor sections in sterile water + DHA + anti-PD-1 and A. muciniphila + DHA + anti-PD-1 groups (scale bar, 100 or 50 µm). (H) Average optical density of CD8⁺ T cells in tumors from immunohistochemical staining. Data are represented as mean ± SD (n = 5 per group), *P < 0.05. (I) ELISA results of tumor tissues from A. muciniphila + DHA + anti-PD-1 and sterile water + DHA + anti-PD-1 groups (IL-2, IFN-γ, IL-10, and TNF-α). Data are represented as mean ± SD (n = 4 per group). *P < 0.05. ns, no significance.

Fig.4 YAP1 decreased the abundance of A. muciniphila. (A) Schematic of liver tumor in situ model in Yap1^Flox and Yap1^LKO mice induced by DEN/TCPOBOP. (B, C) Amount of total bacteria and the abundance of A. muciniphila in Yap1^LKO and Yap1^Flox mice with liver tumors at 7, 11, 15, 19, and 23 weeks by real-time PCR. Data are represented as mean ± SD. *P < 0.05. ns, no significance. (D) Schematic of the reduction of A. muciniphila in the colon induced by ATB and gavage of A. muciniphila in Yap1^LKO and Yap1^Flox mice. (E) Amount of total bacteria and A. muciniphila abundance in Yap1^LKO and Yap1^Flox mice treated with ATB and gavage of A. muciniphila by real-time PCR. Data are represented as mean ± SD. *P < 0.05. ns, no significance. (F) Shannon’s index plot showing the bacterial diversity in Yap1^LKO and Yap1^Flox mice with liver tumors. (G, H) Compositions of the bacterial community (top 10) at the phylum and genus levels in Yap1^Flox and Yap1^LKO mice with liver tumors. (I) Principal coordinate analysis of bacterial community differences (n = 4 per group). (J) Histogram of LDA between Yap1^Flox and Yap1^LKO mice with liver tumors.

Fig.5 Decreased abundance of A. muciniphila in the colon by YAP1 related to bile acid metabolism. (A) Schematic of liver tumor in situ model in Yap1^Flox and Yap1^LKO mice induced by DEN/TCPOBOP and bile acid detection. (B) Principal component analysis representing the reliability of the results (n = 10 per group). (C) Relative bile acid values of liver in Yap1^Flox and Yap1^LKO mice with liver tumors by LC–MS. (D–F) Differences in bile acids in the liver, serum, and colonic contents between Yap1^Flox and Yap1^LKO mice with liver tumors. Data are represented as mean ± SD (n = 8 per group). *P < 0.05. (G) Correlation analysis between the abundance of microflora at the phylum level and bile acids.

Fig.6 DHA depressed YAP1 expression, leading to the increased abundance of A. muciniphila. (A) Schematic of liver tumor in situ model in Yap1^Flox and Yap1^LKO mice induced by DEN/TCPOBOP and treated with DHA. (B) Amount of total bacteria and the abundance of A. muciniphila in the feces of Yap1^Flox and Yap1^LKO mice treated with DHA, as determined by real-time PCR assay. Data are represented as mean ± SD, *P < 0.05. (C) The heterotopic tumor model was induced by Hepa1-6 cells in the decreased abundance of A. muciniphila mice treated with ATB. The mice were treated with DHA, and A. muciniphila or sterile water was administered by oral gavage after stopping the ATB treatment. (D) Relative bile acid values of colonic contents in tumor-bearing mice treated with DHA from A. muciniphila or sterile water groups by LC–MS. (E and F) Differences in bile acids in tumor-bearing mice treated with DHA from A. muciniphila or sterile water groups. Data are represented as mean ± SD (n = 5 per group). *P < 0.05.

Fig.7 A. muciniphila increased CD8⁺ T cell numbers in the spleen and tumor niche during DHA treatment. (A) The heterotopic tumor model was induced by Hepa1-6 cells in the decreased abundance of A. muciniphila mice treated with ATB. The mice were treated with DHA, and A. muciniphila or sterile water was administered by oral gavage after stopping the ATB treatment. (B, C) Representative liver tumor pictures, weight and volume of tumors in sterile water + DHA and A. muciniphila + DHA groups. Data are represented as mean ± SD (n = 4 per group). *P < 0.05. (D, E) Representative pictures and quantification of CD8⁺ T in CD3⁺ T cells in blood and spleen by flow cytometry analysis. Data are represented as mean ± SD (n = 4 per group). *P < 0.05. ns, no significance. (F) Representative pictures of H&E and immunohistochemical staining of CD8 from tumor sections in sterile water + DHA and A. muciniphila + DHA groups (scale bar, 100 or 50 µm). (G) Average optical density of CD8⁺ T cells in tumors from immunohistochemical staining. Data are represented as mean ± SD (n = 4 per group). *P < 0.05. (H) ELISA results of tumor tissues from sterile water + DHA and A. muciniphila + DHA groups (IL-2, IFN-γ, IL-10, and TNF-α). Data are represented as mean ± SD (n = 4 per group). *P < 0.05. ns, no significance.

Fig.8

Fig.9 Mechanism of DHA sensitizing HCC to anti-PD-1 immunotherapy. YAP1 in liver tumor cells inhibited the abundance of A. muciniphila in the colon by regulating hepatic bile acid metabolism (such as TCDCA, GCA, and TCA). Anti-PD-1 treatment increased YAP1 expression in liver tumor cells and decreased the abundance of A. muciniphila. DHA increased the abundance of A. muciniphila by inhibiting YAP1 expression and promoted the efficacy of anti-PD-1 in mice with liver tumors.

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