IL-15 Plus Thymosin α1 Reduces Senescent Hepatic CD8<sup>+</sup> T Cells in Hepatocellular Carcinoma via PI3K/AKT Suppression.
This preclinical study investigated whether combining interleukin-15 (IL-15) with thymosin alpha 1 (Tα1) could reverse CD8+ T cell immunosenescence and enhance antitumor immunity in hepatocellular carcinoma (HCC). Using an orthotopic HCC model in aged C57BL/6 mice (22–26 months old), animals were randomized to saline, IL-15 alone, Tα1 alone, or combination therapy. The study found that the combination treatment significantly suppressed tumor growth and prolonged survival compared to either agent alone or control. Mechanistically, combination therapy reduced the proportion of senescent CD8+ T cells, expanded activated effector populations, and upregulated cytotoxic markers such as granzyme B, perforin, and interferon-gamma. Transcriptomic and Western blot analyses indicated that the combination suppressed chronically overactivated PI3K/AKT signaling in hepatic CD8+ T cells — an effect confirmed by in vitro experiments using primary human CD8+ T cells co-cultured with Huh7 hepatoma cells, where the AKT agonist SC79 reversed the therapeutic benefit. Key limitations include the exclusively preclinical design (no human clinical data), use of a single mouse HCC model, and the need for further validation of the proposed mechanism in clinical settings.
Why this grade: All in vivo efficacy and survival data derive from an aged mouse orthotopic HCC model; in vitro human cell data are supportive but no human clinical trial was conducted.
Background and aim CD8 + T cell immunosenescence drives hepatocellular carcinoma (HCC) progression and impedes therapeutic efficacy. We hypothesized that combining interleukin-15 (IL-15), which rescues senescent CD8 + T cells peripherally, with thymosin alpha 1 (Tα1), which replenishes the T cell pool via thymic rejuvenation, may synergistically overcome immunosenescence and enhance antitumor immunity in HCC. Methods 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. Tumor progression was monitored by bioluminescence imaging, survival analysis, and histopathology. Hepatic CD8 + T cell phenotype and function were evaluated by multicolor flow cytometry, immunofluorescence, transcriptomic sequencing, and Western blotting. In vitro validation used primary human CD8 + T cells co-cultured with Huh7 hepatoma cells. Results The combination therapy significantly suppressed tumor growth and prolonged survival. 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. Transcriptomic and protein-level analyses revealed that the combination attenuated chronically overactivated phosphatidylinositol 3-kinase/protein kinase B signaling in hepatic CD8 + T cells. A protein kinase B agonist, SC79, abrogated these therapeutic effects in vitro, confirming pathway suppression as the key mechanism. Conclusions Combined IL-15 and Tα1 therapy reverses CD8 + T cell senescence and enhances antitumor immunity in HCC through suppression of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway.
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