Aging-induced hepatocyte CD44 drives IL6/STAT3 signaling and associates with impaired neighboring T cell function

bioRxiv (Cold Spring Harbor Laboratory) 2025

Armin Gandhi; Kathry Lande; Yichen Li; Filipe A. Hoffman; Michael LaPorte; Shirong Tan; Garrett Evensen; Benji Portillo; Marcos G. Teneche; Rouven Arnold; Adarsh Rajesh; Jessica Proulx; Shanshan Yin; Aaron Havas; Charlene Miciano; Qian Yang; Elizabeth W. Smoot; Sainath Mamde; Andrew Davis; Kevin Yip; Allen Wang; Bing Ren; April E. Williams; Susan M. Kaech; Peter D. Adams

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 are not well defined. This study investigates the role of CD44, a marker of liver tumor-initiating cells (TIC), in age-associated liver pathophysiology. Aged livers showed accumulation of CD44-expressing hepatocytes exhibiting enrichment of immune modulatory genes and activation of the immunosuppressive IL6/JAK/STAT3 pathway. Indeed, in adoptive transfer assays, antigen-exposed CD8+ T cells mounted a lower IFN-γ response in aged livers than in young livers, indicating an immunosuppressive aged milieu. Concordantly, spatial analyses showed that the proximal neighbourhoods of Cd44-expressing hepatocytes are enriched in T cells exhibiting reduced cytokine and chemokine gene expression. Finally, hepatocyte-specific knock out of Cd44 mitigated the IL6/JAK/STAT3 gene signature in aged livers. Overall, these findings suggest that CD44 expression in aged hepatocytes promotes activation of the immunosuppressive IL6/JAK/STAT3 pathway and this is associated with impaired T cell effector function.

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