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

AbstractThe 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, andAkkermansia muciniphila abundance decreased in the colon. The response to anti-PD-1 treatment is associated withA. muciniphila abundance in many tumors. However, the interaction betweenA. muciniphila abundance and YAP1 expression remains unclear in HCC. Here, anti-PD-1 treatment decreasedA. muciniphila abundance in the colon, but increased YAP1 expression in the tumor cells by mice with liver tumorsin situ. Mechanistically, hepatocyte-specificYap1 knockout (Yap1LKO) maintained bile acid homeostasis in the liver, resulting in an increased abundance ofA. muciniphila in the colon.Yap1 knockout enhanced anti-PD-1 efficacy. Therefore, YAP1 inhibition is a potential target for increasingA. muciniphila abundance to promote anti-PD-1 efficacy in liver tumors. Dihydroartemisinin (DHA), acting as YAP1 inhibitor, increasedA. 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.
Source: Frontiers of Medicine - Category: General Medicine Source Type: research