Aging-induced hepatocyte CD44 drives IL6/STAT3 signaling that associates with impaired function of neighboring T cells

Abstract

Liver cancer incidences increase dramatically beyond 55 years of age, suggesting that age-associated changes contribute critically to tumor initiation. However, the mechanisms linking liver aging and cancer initiation remain incompletely defined. This study investigated the role of CD44, a marker of liver tumor-initiating cells (TICs), in age-associated liver pathophysiology. To define the role of CD44 in aged livers, we profiled CD44-expressing hepatocytes in young and aged livers by targeted and unbiased -omics methods, assessed their number and relationship to neighboring T cells by spatial transcriptomics, and validated key findings using hepatocyte-specific Cd44 knockout. Aged livers showed an accumulation of CD44-expressing hepatocytes enriched for immune modulatory genes and activation of the immunosuppressive IL-6/JAK/STAT3 pathway. Consistent with an immunosuppressive aged milieu, following their adoptive transfer antigen-exposed CD8+ T cells mounted a lower IFN-γ response in aged livers than in young livers. Concordantly, spatial analyses showed that neighborhoods proximal to Cd44 -expressing hepatocytes are enriched in T cells exhibiting reduced cytokine and chemokine gene expression. Finally, hepatocyte-specific knockout of Cd44 mitigated the IL-6/JAK/STAT3 gene signature in aged livers. Overall, these findings suggest that CD44 expression in aged hepatocytes promotes activation of the immunosuppressive IL-6/JAK/STAT3 pathway associated with impaired T cell effector function, potentially, contributing to the increased incidence of liver cancer with age.