Hepatocellular carcinoma escapes immune surveillance through deceiving thymus into recalling peripheral activated CD8+ T cells

Hepatocellular carcinoma escapes immune surveillance through deceiving thymus into recalling peripheral activated CD8+ T cells

The role of thymic epithelial cells (TECs) in eliminating self-reactive T cells through the presentation of self-antigens is well-established. However, it remains unclear whether TECs can eliminate tumor-reactive CD8+ T cells by presenting tumor antigens. In this study, we observed that CD73+ Granzy...

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Main Authors: Qiaoting Hu, Xuefeng Wang, Yundan You, Jun Liu, Bin Lan, Fangfang Chen, Hong Wen, Haili Cheng, Weibin Zhuo, Ting Xu, Jingxian Zheng, Yuchuan Jiang, Xiaojie Wang, Jing Lin, Zengqing Guo, Sha Huang, Gang Chen, Yu Chen, Jingfeng Liu
Format: Article
Language:English
Published: Elsevier 2025-09-01
Series:Neoplasia: An International Journal for Oncology Research
Subjects:
HCC
CD8+ T cells
CCR7
Thymic epithelial cells
Activation-induced cell death (AICD)
Online Access:http://www.sciencedirect.com/science/article/pii/S1476558625000909
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Summary:The role of thymic epithelial cells (TECs) in eliminating self-reactive T cells through the presentation of self-antigens is well-established. However, it remains unclear whether TECs can eliminate tumor-reactive CD8+ T cells by presenting tumor antigens. In this study, we observed that CD73+ Granzyme B+ peripheral activated CD8+ T cells undergo apoptosis in the medullary region of the thymus in DEN-CCL4-induced spontaneous HCC mice, but not in the naïve control group. Mechanistically, HCC cells manipulate the thymus to recruit peripheral activated CD8+ T cells through the CCL19/CCL21-CCR7 axis. Additionally, TECs capture antigens from HCC cells for subsequent antigen presentation instead of de novo expressing tumor antigens. When tumor-associated CD8+ T cells homing to the thymus recognize the same tumor antigen presented by TECs, activation-induced cell death (AICD) is initiated in these T cells. Thymectomy redistributes CD8+ T cells into the tumor focus to suppress HCC growth. Alternatively, both inhibiting CCL19/CCL21 expression of thymic cells using an AMPK activator and blocking CCR7 on CD8+ T cells binding with ligands using Cmp2105 significantly reduces tumor-educated thymus dependent immune evasion. Our findings collectively demonstrate that HCC manipulates the thymus to trigger immune escape; pharmacologically targeting CCL19/CCL21-CCR7 axis to inhibit thymus homing can increase CD8+ T cells in the tumor microenvironment.
ISSN:1476-5586

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