IL-15 Plus Thymosin α1 Reduces Senescent Hepatic CD8+ T Cells in Hepatocellular Carcinoma via PI3K/AKT Suppression.

Preclinical study using an orthotopic hepatocellular carcinoma model in aged mice and in vitro human cell co-culture experiments.

“An orthotopic HCC model was established in aged C57BL/6 mice (22–26 months), randomly assigned to receive saline, IL‐15, Tα1, or combined therapy.”

Aged C57BL/6 mice (22–26 months) and primary human CD8+ T cells from elderly donors (≥ 65 years old).

“C57BL/6 mice (aged 22–26 months) were obtained from GemPharmatech Co. Ltd. (Jiangsu, China).”

44 mice divided into four groups of 11 each; in vitro experiments used 3 independent experiments.

“Forty‐four mice were randomly divided into four groups, with 11 mice in each group.”

Treatment continued for 14 days post-inoculation, with mice sacrificed on day 14.

“The same treatment regimen was resumed 1 day post‐inoculation and continued for 14 days.”

Combined IL-15 and Tα1 therapy suppressed tumor growth and prolonged survival compared to control.

“The combination therapy significantly suppressed tumor growth and prolonged survival.”

The combination therapy reduced the proportion of senescent CD8+ T cells and expanded activated effector populations.

“It reduced the proportion of senescent CD8+ T cells while expanding activated effector populations, enhanced proliferative capacity, and upregulated cytotoxic mediators including granzyme B, perforin, and interferon‐gamma.”

The therapeutic effects were mediated by the suppression of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway.

“Transcriptomic and protein‐level analyses revealed that the combination attenuated chronically overactivated phosphatidylinositol 3‐kinase/protein kinase B signaling in hepatic CD8+ T cells.”

The study focused primarily on CD8+ T cells, leaving the contributions of other immune cell populations such as NK cells, dendritic cells, and regulatory T cells unexplored.

“We acknowledge that this study focused primarily on CD8+ T cells, whereas both IL‐15 and Tα1 exert pleiotropic immunomodulatory effects on other immune cell populations.”