Syngeneic natural killer cell therapy activates dendritic and T cells in metastatic lungs and effectively treats low-burden metastases
Natural killer (NK) cells can control metastasis through cytotoxicity and IFN-γ production independently of T cells in experimental metastasis mouse models. The inverse correlation between NK activity and metastasis incidence supports a critical role for NK cells in human metastatic surveillance. Ho...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2025-01-01
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| Online Access: | https://elifesciences.org/articles/99010 |
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| author | Shih-Wen Huang Yein-Gei Lai Hao-Ting Liao Chin-Ling Chang Ruo-Yu Ma Yung-Hsiang Chen Yae-Huei Liou Zhen-Qi Wu Yu-Chen Wu Ko-Jiunn Liu Yen-Tsung Huang Jen-Lung Yang Ming-Shen Dai Nan-Shih Liao |
| author_facet | Shih-Wen Huang Yein-Gei Lai Hao-Ting Liao Chin-Ling Chang Ruo-Yu Ma Yung-Hsiang Chen Yae-Huei Liou Zhen-Qi Wu Yu-Chen Wu Ko-Jiunn Liu Yen-Tsung Huang Jen-Lung Yang Ming-Shen Dai Nan-Shih Liao |
| author_sort | Shih-Wen Huang |
| collection | DOAJ |
| description | Natural killer (NK) cells can control metastasis through cytotoxicity and IFN-γ production independently of T cells in experimental metastasis mouse models. The inverse correlation between NK activity and metastasis incidence supports a critical role for NK cells in human metastatic surveillance. However, autologous NK cell therapy has shown limited benefit in treating patients with metastatic solid tumors. Using a spontaneous metastasis mouse model of MHC-I+ breast cancer, we found that transfer of IL-15/IL-12-conditioned syngeneic NK cells after primary tumor resection promoted long-term survival of mice with low metastatic burden and induced a tumor-specific protective T cell response that is essential for the therapeutic effect. Furthermore, NK cell transfer augments activation of conventional dendritic cells (cDCs), Foxp3-CD4+ T cells and stem cell-like CD8+ T cells in metastatic lungs, to which IFN-γ of the transferred NK cells contributes significantly. These results imply direct interactions between transferred NK cells and endogenous cDCs to enhance T cell activation. We conducted an investigator-initiated clinical trial of autologous NK cell therapy in six patients with advanced cancer and observed that the NK cell therapy was safe and showed signs of effectiveness. These findings indicate that autologous NK cell therapy is effective in treating established low burden metastases of MHC-I+ tumor cells by activating the cDC-T cell axis at metastatic sites. |
| format | Article |
| id | doaj-art-4c0c2e1a0d9541199d4a0472222d785b |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-4c0c2e1a0d9541199d4a0472222d785b2025-01-21T11:16:02ZengeLife Sciences Publications LtdeLife2050-084X2025-01-011310.7554/eLife.99010Syngeneic natural killer cell therapy activates dendritic and T cells in metastatic lungs and effectively treats low-burden metastasesShih-Wen Huang0Yein-Gei Lai1https://orcid.org/0000-0002-7342-4395Hao-Ting Liao2https://orcid.org/0009-0008-9048-7698Chin-Ling Chang3Ruo-Yu Ma4Yung-Hsiang Chen5Yae-Huei Liou6Zhen-Qi Wu7Yu-Chen Wu8Ko-Jiunn Liu9Yen-Tsung Huang10Jen-Lung Yang11Ming-Shen Dai12Nan-Shih Liao13https://orcid.org/0000-0003-3707-4145Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan; Molecular and Cell Biology, Taiwan International Graduate Program, Academia Sinica and Graduate Institute of Life Science, National Defense Medical Center, Taipei, TaiwanInstitute of Molecular Biology, Academia Sinica, Taipei, TaiwanInstitute of Molecular Biology, Academia Sinica, Taipei, Taiwan; Department of Life Sciences, National Central University, Taoyuan, TaiwanInstitute of Molecular Biology, Academia Sinica, Taipei, TaiwanInstitute of Molecular Biology, Academia Sinica, Taipei, TaiwanInstitute of Molecular Biology, Academia Sinica, Taipei, TaiwanInstitute of Molecular Biology, Academia Sinica, Taipei, TaiwanInstitute of Molecular Biology, Academia Sinica, Taipei, TaiwanNational Institute of Cancer Research, National Health Research Institutes, Tainan, TaiwanNational Institute of Cancer Research, National Health Research Institutes, Tainan, TaiwanInstitute of Statistical Science, Academia Sinica, Taipei, TaiwanInstitute of Molecular Biology, Academia Sinica, Taipei, TaiwanDepartment of Hematology-Oncology, Tri-Service General Hospital, Taipei, TaiwanInstitute of Molecular Biology, Academia Sinica, Taipei, Taiwan; Molecular and Cell Biology, Taiwan International Graduate Program, Academia Sinica and Graduate Institute of Life Science, National Defense Medical Center, Taipei, TaiwanNatural killer (NK) cells can control metastasis through cytotoxicity and IFN-γ production independently of T cells in experimental metastasis mouse models. The inverse correlation between NK activity and metastasis incidence supports a critical role for NK cells in human metastatic surveillance. However, autologous NK cell therapy has shown limited benefit in treating patients with metastatic solid tumors. Using a spontaneous metastasis mouse model of MHC-I+ breast cancer, we found that transfer of IL-15/IL-12-conditioned syngeneic NK cells after primary tumor resection promoted long-term survival of mice with low metastatic burden and induced a tumor-specific protective T cell response that is essential for the therapeutic effect. Furthermore, NK cell transfer augments activation of conventional dendritic cells (cDCs), Foxp3-CD4+ T cells and stem cell-like CD8+ T cells in metastatic lungs, to which IFN-γ of the transferred NK cells contributes significantly. These results imply direct interactions between transferred NK cells and endogenous cDCs to enhance T cell activation. We conducted an investigator-initiated clinical trial of autologous NK cell therapy in six patients with advanced cancer and observed that the NK cell therapy was safe and showed signs of effectiveness. These findings indicate that autologous NK cell therapy is effective in treating established low burden metastases of MHC-I+ tumor cells by activating the cDC-T cell axis at metastatic sites.https://elifesciences.org/articles/99010natural killer cellmetastatic cancerdendritic cellT cell |
| spellingShingle | Shih-Wen Huang Yein-Gei Lai Hao-Ting Liao Chin-Ling Chang Ruo-Yu Ma Yung-Hsiang Chen Yae-Huei Liou Zhen-Qi Wu Yu-Chen Wu Ko-Jiunn Liu Yen-Tsung Huang Jen-Lung Yang Ming-Shen Dai Nan-Shih Liao Syngeneic natural killer cell therapy activates dendritic and T cells in metastatic lungs and effectively treats low-burden metastases eLife natural killer cell metastatic cancer dendritic cell T cell |
| title | Syngeneic natural killer cell therapy activates dendritic and T cells in metastatic lungs and effectively treats low-burden metastases |
| title_full | Syngeneic natural killer cell therapy activates dendritic and T cells in metastatic lungs and effectively treats low-burden metastases |
| title_fullStr | Syngeneic natural killer cell therapy activates dendritic and T cells in metastatic lungs and effectively treats low-burden metastases |
| title_full_unstemmed | Syngeneic natural killer cell therapy activates dendritic and T cells in metastatic lungs and effectively treats low-burden metastases |
| title_short | Syngeneic natural killer cell therapy activates dendritic and T cells in metastatic lungs and effectively treats low-burden metastases |
| title_sort | syngeneic natural killer cell therapy activates dendritic and t cells in metastatic lungs and effectively treats low burden metastases |
| topic | natural killer cell metastatic cancer dendritic cell T cell |
| url | https://elifesciences.org/articles/99010 |
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