Effect and Molecular Mechanisms of Haizao Yuhu Tang in Ameliorating Immune Escape in Mice with Papillary Thyroid Carcinoma via Regulation of CD8+T Cell Exhaustion
10.13422/j.cnki.syfjx.20260913
- VernacularTitle:海藻玉壶汤调节CD8+T细胞耗竭对甲状腺乳头状癌小鼠免疫逃逸的影响及分子机制
- Author:
Ruyu CHEN
1
;
Ziyang JIANG
1
;
Xueying CHEN
2
;
Fengnuan ZHANG
2
;
Tianshu GAO
2
Author Information
1. The First Clinical College， Liaoning University of Traditional Chinese Medicine（TCM）， Shenyang 110847，China
2. Affiliated Hospital of Liaoning University of TCM， Shenyang 110033，China
- Publication Type:Journal Article
- Keywords:
Haizao Yuhu Tang;
papillary thyroid carcinoma;
CD8-positive T lymphocyte （CD8+T） cell exhaustion;
immune escape
- From:
Chinese Journal of Experimental Traditional Medical Formulae
2026;32(23):47-58
- CountryChina
- Language:Chinese
-
Abstract:
ObjectiveTo investigate the mechanism by which Haizao Yuhu Tang regulates the nuclear receptor subfamily 4 group A member 1 （NR4A1）signaling pathway to modulate CD8-positive T lymphocyte （CD8+T） cell exhaustion-mediated immune escape in transgenic mice with papillary thyroid carcinoma （PTC）. MethodsSixty C57BL/6J mice carrying the conditional BRAFV600E point mutation were randomly assigned to five groups （n=12）： Model， low-dose （7.28 g·kg-1·d-1） Haizao Yuhu Tang， medium-dose （14.56 g·kg-1·d-1） Haizao Yuhu Tang， high-dose （29.12 g·kg-1·d-1） Haizao Yuhu Tang， and vemurafenib （PLX4032， 0.02 g·kg-1·d-1）. In addition， 12 BRAFV600E-negative mice were selected as the control group. All the groups received continuous intervention for 8 weeks. After treatment， the thyroid tumor weight and volume of mice in each group were measured. Hematoxylin and eosin （HE） staining was performed to observe the morphological characteristics of thyroid tumors. Enzyme-linked immunosorbent assay （ELISA） was adopted to quantify the serum levels of interferon-γ （IFN-γ）， interleukin-2 （IL-2）， tumor necrosis factor-α （TNF-α）， C-X-C motif chemokine ligand 9 （CXCL9）， and C-X-C motif chemokine ligand 10 （CXCL10）. Flow cytometry was employed to determine the proportion of cytotoxic CD8+T cells in the tumor tissue. Western blot and real-time PCR were employed to determine the protein and mRNA levels， respectively， of molecules related to the NR4A1 signaling pathway. ResultsCompared with the control group， the model group showed significantly increased thyroid tumor volume and weight （P<0.01）. Compared with the model group， the low-dose， medium-dose， and high-dose Haizao Yuhu Tang groups and the vemurafenib group exhibited varying degrees of reduction in thyroid tumor volume and weight （P<0.05， P<0.01）， with the medium-dose Haizao Yuhu Tang group and the vemurafenib group showing the most pronounced therapeutic effects （P<0.01）. Compared with the model group， the low-dose， medium-dose， and high-dose Haizao Yuhu Tang groups and the vemurafenib group showed increased serum levels of IFN-γ， IL-2， TNF-α， CXCL9， and CXCL10， decreased mRNA and protein levels of NR4A1， Programmed cell death-1 （PD-1）， and Programmed cell death-ligand 1 （PD-L1）， and enhanced cytotoxic activity of CD8+T cells （P<0.05， P<0.01） Among these groups， the medium-dose Haizao Yuhu Tang group exhibited the optimal therapeutic effects. In addition， compared with that in the model group， T-cell factor-1 （TCF-1） expression was increased in the low-dose， medium-dose， and high-dose Haizao Yuhu Tang groups （P<0.01）， whereas no significant change in TCF-1 expression was observed in the vemurafenib group. ConclusionHaizao Yuhu Tang may restore the cytotoxic function of CD8+T cells by inhibiting the NR4A1 signaling pathway， thereby suppressing immune evasion in PTC and delaying PTC growth.
