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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Elsevier
2025-09-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558625000909 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Qiaoting Hu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2dd18cc477d843d2ad9c9bef69d1f027 |
| institution | DOAJ |
| issn | 1476-5586 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj-art-2dd18cc477d843d2ad9c9bef69d1f0272025-08-20T02:45:14ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862025-09-016710121010.1016/j.neo.2025.101210Hepatocellular carcinoma escapes immune surveillance through deceiving thymus into recalling peripheral activated CD8+ T cellsQiaoting Hu0Xuefeng Wang1Yundan You2Jun Liu3Bin Lan4Fangfang Chen5Hong Wen6Haili Cheng7Weibin Zhuo8Ting Xu9Jingxian Zheng10Yuchuan Jiang11Xiaojie Wang12Jing Lin13Zengqing Guo14Sha Huang15Gang Chen16Yu Chen17Jingfeng Liu18Depatment of medical oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital (Fujian Branch of Fudan University Shanghai Cancer Center), Fuzhou, Fujian, PR China; Innovation center for cancer research, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, PR ChinaDepatment of medical oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital (Fujian Branch of Fudan University Shanghai Cancer Center), Fuzhou, Fujian, PR China; Innovation center for cancer research, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, PR China; Interdisciplinary institute for medical engineering, Fuzhou University, Fuzhou, Fujian, PR China; Corresponding authors.Depatment of intensive care unit, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, PR ChinaDepatment of medical oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital (Fujian Branch of Fudan University Shanghai Cancer Center), Fuzhou, Fujian, PR ChinaDepatment of medical oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital (Fujian Branch of Fudan University Shanghai Cancer Center), Fuzhou, Fujian, PR China; Innovation center for cancer research, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, PR ChinaDepatment of pathology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, PR ChinaDepatment of pathology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, PR ChinaDepatment of pathology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, PR ChinaInnovation center for cancer research, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, PR China; Department of Hepatopancreatobiliary Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, PR ChinaDepartment of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, PR ChinaDepatment of medical oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital (Fujian Branch of Fudan University Shanghai Cancer Center), Fuzhou, Fujian, PR ChinaDepartment of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, PR ChinaDepatment of medical oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital (Fujian Branch of Fudan University Shanghai Cancer Center), Fuzhou, Fujian, PR ChinaDepatment of medical oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital (Fujian Branch of Fudan University Shanghai Cancer Center), Fuzhou, Fujian, PR ChinaDepatment of medical oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital (Fujian Branch of Fudan University Shanghai Cancer Center), Fuzhou, Fujian, PR ChinaDepatment of medical oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital (Fujian Branch of Fudan University Shanghai Cancer Center), Fuzhou, Fujian, PR ChinaDepatment of pathology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, PR China; Corresponding authors.Depatment of medical oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital (Fujian Branch of Fudan University Shanghai Cancer Center), Fuzhou, Fujian, PR China; Interdisciplinary institute for medical engineering, Fuzhou University, Fuzhou, Fujian, PR China; Corresponding authors.Depatment of medical oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital (Fujian Branch of Fudan University Shanghai Cancer Center), Fuzhou, Fujian, PR China; Interdisciplinary institute for medical engineering, Fuzhou University, Fuzhou, Fujian, PR China; Department of Hepatopancreatobiliary Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, PR China; Corresponding authors.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.http://www.sciencedirect.com/science/article/pii/S1476558625000909HCCCD8+ T cellsCCR7Thymic epithelial cellsActivation-induced cell death (AICD) |
| spellingShingle | 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 Hepatocellular carcinoma escapes immune surveillance through deceiving thymus into recalling peripheral activated CD8+ T cells Neoplasia: An International Journal for Oncology Research HCC CD8+ T cells CCR7 Thymic epithelial cells Activation-induced cell death (AICD) |
| title | Hepatocellular carcinoma escapes immune surveillance through deceiving thymus into recalling peripheral activated CD8+ T cells |
| title_full | Hepatocellular carcinoma escapes immune surveillance through deceiving thymus into recalling peripheral activated CD8+ T cells |
| title_fullStr | Hepatocellular carcinoma escapes immune surveillance through deceiving thymus into recalling peripheral activated CD8+ T cells |
| title_full_unstemmed | Hepatocellular carcinoma escapes immune surveillance through deceiving thymus into recalling peripheral activated CD8+ T cells |
| title_short | Hepatocellular carcinoma escapes immune surveillance through deceiving thymus into recalling peripheral activated CD8+ T cells |
| title_sort | hepatocellular carcinoma escapes immune surveillance through deceiving thymus into recalling peripheral activated cd8 t cells |
| topic | HCC CD8+ T cells CCR7 Thymic epithelial cells Activation-induced cell death (AICD) |
| url | http://www.sciencedirect.com/science/article/pii/S1476558625000909 |
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