Intestinal Akkermansia muciniphila complements the efficacy of PD1 therapy in MAFLD-related hepatocellular carcinoma
Xiaomeng Wu, Ying Fan, Katherine Po Sin Chung, Carmen Oi Ning Leung, Rainbow Wing Hei Leung, Karl Kam Hei So, Martina Mang Leng Lei, Wing Ki Chau, Man Tong, Jun Yu, Dai Wei, William Chi Shing Tai, Stephanie Ma, Yin Lu, Terence K. Lee
Abstract
Immune checkpoint inhibitors are not effective for metabolic dysfunction-associated fatty liver disease (MAFLD)-hepatocellular carcinoma (HCC) patients, and identifying the key gut microbiota that contributes to immune resistance in these patients is crucial. Analysis using 16S rRNA sequencing reveals a decrease in Akkermansia muciniphila (Akk) during MAFLD-promoted HCC development. Administration of Akk ameliorates liver steatosis and effectively attenuates the tumor growth in orthotopic MAFLD-HCC mouse models. Akk repairs the intestinal lining, with a decrease in the serum lipopolysaccharide (LPS) and bile acid metabolites, along with decrease in the populations of monocytic myeloid-derived suppressor cells (m-MDSCs) and M2 macrophages. Akk in combination with PD1 treatment exerts maximal growth-suppressive effect in multiple MAFLD-HCC mouse models with increased infiltration and activation of T cells. Clinically, low Akk levels are correlated with PD1 resistance and poor progression-free survival. In conclusion, Akk is involved in the immune resistance of MAFLD-HCC and serves as a predictive biomarker for PD1 response in HCC.