Natural lung-tropic TH9 cells: a sharp weapon for established lung metastases
Background Lung metastasis remains the primary cause of tumor-related mortality, with limited treatment options and unsatisfactory efficacy. In preclinical studies, T helper 9 (TH9) cells have shown promise in treating solid tumors. However, it is unclear whether TH9 cells can tackle more challengin...
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BMJ Publishing Group
2024-12-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/12/e009629.full |
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| author | Tao Chen Hao Zhou Shuming Li Nong Lin Yixuan Feng Zhijian Cai Chenxiao Qiao Eloy Yinwang Shengdong Wang Xuehuan Wen Xiangang Jin Yucheng Xue Wenkan Zhang Xianchang Zeng Zenan Wang Hangxiang Sun Lifeng Jiang Hengyuan Li Binghao Li Zhaoming Ye |
| author_facet | Tao Chen Hao Zhou Shuming Li Nong Lin Yixuan Feng Zhijian Cai Chenxiao Qiao Eloy Yinwang Shengdong Wang Xuehuan Wen Xiangang Jin Yucheng Xue Wenkan Zhang Xianchang Zeng Zenan Wang Hangxiang Sun Lifeng Jiang Hengyuan Li Binghao Li Zhaoming Ye |
| author_sort | Tao Chen |
| collection | DOAJ |
| description | Background Lung metastasis remains the primary cause of tumor-related mortality, with limited treatment options and unsatisfactory efficacy. In preclinical studies, T helper 9 (TH9) cells have shown promise in treating solid tumors. However, it is unclear whether TH9 cells can tackle more challenging situations, such as established lung metastases. Moreover, comprehensive exploration into the nuanced biological attributes of TH9 cells is imperative to further unravel their therapeutic potential.Methods We adoptively transferred TH1, TH9, and TH17 cells into subcutaneous, in situ, and established lung metastases models of osteosarcoma and triple-negative breast cancer, respectively, comparing their therapeutic efficacy within each distinct model. We employed flow cytometry and an in vivo imaging system to evaluate the accumulation patterns of TH1, TH9, and TH17 cells in the lungs after transfusion. We conducted bulk RNA sequencing on in vitro differentiated TH9 cells to elucidate the chemokine receptor CXCR4, which governs their heightened pulmonary tropism relative to TH1 and TH17 cell counterparts. Using Cd4cre Cxcr4 flox/flox mice, we investigate the effects of CXCR4 on the lung tropism of TH9 cells. We performed mass spectrometry to identify the E3 ligase responsible for CXCR4 ubiquitination and elucidated the mechanism governing CXCR4 expression within TH9 cellular milieu. Ultimately, we analyzed the tumor immune composition after TH9 cell transfusion and evaluated the therapeutic efficacy of adjunctive anti-programmed cell death protein-1 (PD-1) therapy in conjunction with TH9 cells.Results In this study, we provide evidence that TH9 cells exhibit higher lung tropism than TH1 and TH17 cells, thereby exhibiting exceptional efficacy in combating established lung metastases. CXCR4-CXCL12 axis is responsible for lung tropism of TH9 cells as ablating CXCR4 in CD4+ T cells reverses their lung accumulation. Mechanistically, tumor necrosis factor receptor-associated factor 6 (TRAF6)-driven hyperactivation of NF-κB signaling in TH9 cells inhibited ITCH-mediated ubiquitination of CXCR4, resulting in increased CXCR4 accumulation and enhanced lung tropism of TH9 cells. Besides, TH9 cells’ transfusion significantly improved the immunosuppressed microenvironment. TH9 cells and anti-PD-1 exhibit synergistic effects in tumor control.Conclusions Our findings emphasized the innate lung tropism of TH9 cells driven by the activation of TRAF6, which supports the potential of TH9 cells as a promising therapy for established lung metastases. |
| format | Article |
| id | doaj-art-b92421f8a0604580b6a9ff63fc5af99b |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-b92421f8a0604580b6a9ff63fc5af99b2025-08-20T03:53:02ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-12-01121210.1136/jitc-2024-009629Natural lung-tropic TH9 cells: a sharp weapon for established lung metastasesTao Chen0Hao Zhou1Shuming Li2Nong Lin3Yixuan Feng4Zhijian Cai5Chenxiao Qiao6Eloy Yinwang7Shengdong Wang8Xuehuan Wen9Xiangang Jin10Yucheng Xue11Wenkan Zhang12Xianchang Zeng13Zenan Wang14Hangxiang Sun15Lifeng Jiang16Hengyuan Li17Binghao Li18Zhaoming Ye19Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People`s Republic of ChinaDepartment of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People`s Republic of ChinaDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People`s Republic of ChinaEye Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People`s Republic of ChinaDepartment of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People`s Republic of ChinaDepartment of Respiratory, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Featured Laboratory of Respiratory Immunology and Regenerative Medicine in Universities of Shandong, Jinan Clinical Research Center for Respiratory Disease, Jinan, Shandong, People`s Republic of ChinaDepartment of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People`s Republic of ChinaDepartment of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People`s Republic of ChinaDepartment of Oncology, The Affiliated Cangnan Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People`s Republic of ChinaTaizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Taizhou, Zhejiang, ChinaDepartment of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People`s Republic of ChinaDepartment of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People`s Republic of ChinaInstitute of Immunology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaDepartment of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People`s Republic of ChinaDepartment of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People`s Republic of ChinaOrthopaedic Research Institute, Zhejiang University, Hangzhou, Zhejiang, People`s Republic of ChinaDepartment of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People`s Republic of ChinaDepartment of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People`s Republic of ChinaDepartment of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People`s Republic of ChinaBackground Lung metastasis remains the primary cause of tumor-related mortality, with limited treatment options and unsatisfactory efficacy. In preclinical studies, T helper 9 (TH9) cells have shown promise in treating solid tumors. However, it is unclear whether TH9 cells can tackle more challenging situations, such as established lung metastases. Moreover, comprehensive exploration into the nuanced biological attributes of TH9 cells is imperative to further unravel their therapeutic potential.Methods We adoptively transferred TH1, TH9, and TH17 cells into subcutaneous, in situ, and established lung metastases models of osteosarcoma and triple-negative breast cancer, respectively, comparing their therapeutic efficacy within each distinct model. We employed flow cytometry and an in vivo imaging system to evaluate the accumulation patterns of TH1, TH9, and TH17 cells in the lungs after transfusion. We conducted bulk RNA sequencing on in vitro differentiated TH9 cells to elucidate the chemokine receptor CXCR4, which governs their heightened pulmonary tropism relative to TH1 and TH17 cell counterparts. Using Cd4cre Cxcr4 flox/flox mice, we investigate the effects of CXCR4 on the lung tropism of TH9 cells. We performed mass spectrometry to identify the E3 ligase responsible for CXCR4 ubiquitination and elucidated the mechanism governing CXCR4 expression within TH9 cellular milieu. Ultimately, we analyzed the tumor immune composition after TH9 cell transfusion and evaluated the therapeutic efficacy of adjunctive anti-programmed cell death protein-1 (PD-1) therapy in conjunction with TH9 cells.Results In this study, we provide evidence that TH9 cells exhibit higher lung tropism than TH1 and TH17 cells, thereby exhibiting exceptional efficacy in combating established lung metastases. CXCR4-CXCL12 axis is responsible for lung tropism of TH9 cells as ablating CXCR4 in CD4+ T cells reverses their lung accumulation. Mechanistically, tumor necrosis factor receptor-associated factor 6 (TRAF6)-driven hyperactivation of NF-κB signaling in TH9 cells inhibited ITCH-mediated ubiquitination of CXCR4, resulting in increased CXCR4 accumulation and enhanced lung tropism of TH9 cells. Besides, TH9 cells’ transfusion significantly improved the immunosuppressed microenvironment. TH9 cells and anti-PD-1 exhibit synergistic effects in tumor control.Conclusions Our findings emphasized the innate lung tropism of TH9 cells driven by the activation of TRAF6, which supports the potential of TH9 cells as a promising therapy for established lung metastases.https://jitc.bmj.com/content/12/12/e009629.full |
| spellingShingle | Tao Chen Hao Zhou Shuming Li Nong Lin Yixuan Feng Zhijian Cai Chenxiao Qiao Eloy Yinwang Shengdong Wang Xuehuan Wen Xiangang Jin Yucheng Xue Wenkan Zhang Xianchang Zeng Zenan Wang Hangxiang Sun Lifeng Jiang Hengyuan Li Binghao Li Zhaoming Ye Natural lung-tropic TH9 cells: a sharp weapon for established lung metastases Journal for ImmunoTherapy of Cancer |
| title | Natural lung-tropic TH9 cells: a sharp weapon for established lung metastases |
| title_full | Natural lung-tropic TH9 cells: a sharp weapon for established lung metastases |
| title_fullStr | Natural lung-tropic TH9 cells: a sharp weapon for established lung metastases |
| title_full_unstemmed | Natural lung-tropic TH9 cells: a sharp weapon for established lung metastases |
| title_short | Natural lung-tropic TH9 cells: a sharp weapon for established lung metastases |
| title_sort | natural lung tropic th9 cells a sharp weapon for established lung metastases |
| url | https://jitc.bmj.com/content/12/12/e009629.full |
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