Background: Investigate immunoregulation and anti-tumor immunity of FoxP3Tregs after treatment with rapamycin (RAPA/SRL) plus thymalfasin (Zadaxin) and Huaier extract (PS-T) in a hepatocellular carcinoma (HCC) rat model simulating HCC relapse after liver transplant (LT).
Methods: We successfully established a rat model simulating HCC relapse after LT using an optimized chemical induction method with TACROLIMUS, methylprednisolone, and diethylnitrosamine as identified by visible liver nodules and hematoxylin-eosin staining. The model rats were then treated with RAPA, Zadaxin, and PS-T. Immune status changes were analyzed by flow cytometry, and protein expression of Akt and mTOR was determined by western blotting. Cytokines were measured by ELISAs.
Results: Combined therapy by RAPA plus Zadaxin and PS-T obviously alleviated hepatic pathological changes and significantly decreased the levels of FoxP3Tregs in peripheral blood, the spleen, and the liver (P<0.05) and expression of mTOR protein (P<0.01) in the liver, obviously improved survival time (P=0.02). Moreover, the levels of CD8T cells were increased significantly to almost normal levels (P<0.05) in comparison with no SRL monotherapy protocols. Inhibitory cytokines were also decreased in accordance with FoxP3Tregs. Significant decreases of IL-10 and TGF-β were observed after SRL-based therapy (P<0.01) in comparison with the other groups. Serum alpha fetoprotein (AFP) and vascular endothelial growth factor (VEGF) levels were also decreased significantly (P<0.05). FoxP3Tregs showed a negative correlation with CD8 and CD4/CD8T cells and a positive correlation with AFP, and VEGF (P<0.05).
Conclusions: SRL-based therapy reduces FoxP3Tregs to decrease secreted inhibitory cytokines which may enhancement the viability and number of CD8T cells to exert anti-tumor effects that are mainly mediated through the AKT-mTOR signaling pathway.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210174 | PMC |
| http://dx.doi.org/10.21037/atm.2020.03.129 | DOI Listing |
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