TY - JOUR
T1 - Intestinal Akkermansia muciniphila complements the efficacy of PD1 therapy in MAFLD-related hepatocellular carcinoma
AU - Wu, Xue Qian
AU - Ying, Fan
AU - Chung, Katherine Po Sin
AU - Leung, Carmen Oi Ning
AU - Leung, Rainbow Wing Hei
AU - So, Karl Kam Hei
AU - Lei, Martina Mang Leng
AU - Chau, Wing Ki
AU - Tong, Man
AU - Yu, Jun
AU - Wei, Dai
AU - Tai, William Chi Shing
AU - Ma, Stephanie
AU - Lu, Yin Ying
AU - Lee, Terence Kin Wah
N1 - Publisher Copyright:
© 2024 The Author(s)
PY - 2025/1/21
Y1 - 2025/1/21
N2 - 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.
AB - 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.
KW - Akkermansia muciniphila
KW - gut microbiota
KW - HCC
KW - immune checkpoint therapies
KW - MAFLD
UR - http://www.scopus.com/inward/record.url?scp=85215247181&partnerID=8YFLogxK
U2 - 10.1016/j.xcrm.2024.101900
DO - 10.1016/j.xcrm.2024.101900
M3 - Journal article
C2 - 39798567
AN - SCOPUS:85215247181
SN - 2666-3791
VL - 6
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 1
M1 - 101900
ER -