Co-expression of IL-15/IL-15Ra complex enhances NKG2D-CAR T cell-mediated anti-pancreatic cancer immunity by activating the JAK/STAT5 signaling pathway
The application of CAR T therapy has significantly improved the efficacy of hematological tumors. However, there are still some challenges in the treatment of solid tumors, mainly because the complex immune microenvironment affects the proliferation of T cells, making T cells unable to function well...
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Frontiers Media S.A.
2025-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1498706/full |
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| author | Yiran Chen Chenxu Jin Dandan Guo Xinhui Hui Yuzhou Ji Yunhe Huang Min Xue Yaoxin Gao Yaojun Ren Yaojun Ren Haizhen Lin Ying Zhou Wenzheng Jiang |
| author_facet | Yiran Chen Chenxu Jin Dandan Guo Xinhui Hui Yuzhou Ji Yunhe Huang Min Xue Yaoxin Gao Yaojun Ren Yaojun Ren Haizhen Lin Ying Zhou Wenzheng Jiang |
| author_sort | Yiran Chen |
| collection | DOAJ |
| description | The application of CAR T therapy has significantly improved the efficacy of hematological tumors. However, there are still some challenges in the treatment of solid tumors, mainly because the complex immune microenvironment affects the proliferation of T cells, making T cells unable to function well. IL-15 has been reported to be a cytokine that can activate T cells and promote the proliferation and survival of T cells, especially CD8+ T cells. The complex formed by the high-affinity binding of IL-15 and IL-15Rα can bind to IL-2/IL-15Rβ/γ heterodimer on the surface of T cells, thereby activating downstream signaling pathways in T cells. In this study, we explored the activity of NKG2D-CAR T expressing IL-15/IL-15Rα complex (IL15C) on pancreatic cancer. The results of in vitro experiments showed that CAR T cells expressing IL15C had a stronger killing effect on tumor cells and showed a dose-dependent effect. In addition, the proliferation and anti-apoptosis levels of CAR T cells were enhanced after the co-expression of IL15C. IL15C regulates the function of T cells by activating the JAK/STAT5 signaling pathway of T cells. In vivo experiments showed that IL15C-NKG2D-CAR T cells could better inhibit tumor growth than the control group. This study provides a new idea for improving the efficacy of CAR T cells in the treatment of pancreatic cancer. |
| format | Article |
| id | doaj-art-36fcc3d23b1c4cc196223d3b8da8c2d3 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-36fcc3d23b1c4cc196223d3b8da8c2d32025-08-20T03:47:21ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-06-011610.3389/fimmu.2025.14987061498706Co-expression of IL-15/IL-15Ra complex enhances NKG2D-CAR T cell-mediated anti-pancreatic cancer immunity by activating the JAK/STAT5 signaling pathwayYiran Chen0Chenxu Jin1Dandan Guo2Xinhui Hui3Yuzhou Ji4Yunhe Huang5Min Xue6Yaoxin Gao7Yaojun Ren8Yaojun Ren9Haizhen Lin10Ying Zhou11Wenzheng Jiang12Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, ChinaShanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, ChinaShanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, ChinaShanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, ChinaShanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, ChinaShanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, ChinaShanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, ChinaShanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, ChinaShanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, ChinaCollege of Life Science, Xinjiang Normal University, Urumqi, ChinaShanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, ChinaShanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, ChinaShanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, ChinaThe application of CAR T therapy has significantly improved the efficacy of hematological tumors. However, there are still some challenges in the treatment of solid tumors, mainly because the complex immune microenvironment affects the proliferation of T cells, making T cells unable to function well. IL-15 has been reported to be a cytokine that can activate T cells and promote the proliferation and survival of T cells, especially CD8+ T cells. The complex formed by the high-affinity binding of IL-15 and IL-15Rα can bind to IL-2/IL-15Rβ/γ heterodimer on the surface of T cells, thereby activating downstream signaling pathways in T cells. In this study, we explored the activity of NKG2D-CAR T expressing IL-15/IL-15Rα complex (IL15C) on pancreatic cancer. The results of in vitro experiments showed that CAR T cells expressing IL15C had a stronger killing effect on tumor cells and showed a dose-dependent effect. In addition, the proliferation and anti-apoptosis levels of CAR T cells were enhanced after the co-expression of IL15C. IL15C regulates the function of T cells by activating the JAK/STAT5 signaling pathway of T cells. In vivo experiments showed that IL15C-NKG2D-CAR T cells could better inhibit tumor growth than the control group. This study provides a new idea for improving the efficacy of CAR T cells in the treatment of pancreatic cancer.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1498706/fullNKG2DCAR TIL-15pancreatic carcinomaJAK/STAT5 |
| spellingShingle | Yiran Chen Chenxu Jin Dandan Guo Xinhui Hui Yuzhou Ji Yunhe Huang Min Xue Yaoxin Gao Yaojun Ren Yaojun Ren Haizhen Lin Ying Zhou Wenzheng Jiang Co-expression of IL-15/IL-15Ra complex enhances NKG2D-CAR T cell-mediated anti-pancreatic cancer immunity by activating the JAK/STAT5 signaling pathway Frontiers in Immunology NKG2D CAR T IL-15 pancreatic carcinoma JAK/STAT5 |
| title | Co-expression of IL-15/IL-15Ra complex enhances NKG2D-CAR T cell-mediated anti-pancreatic cancer immunity by activating the JAK/STAT5 signaling pathway |
| title_full | Co-expression of IL-15/IL-15Ra complex enhances NKG2D-CAR T cell-mediated anti-pancreatic cancer immunity by activating the JAK/STAT5 signaling pathway |
| title_fullStr | Co-expression of IL-15/IL-15Ra complex enhances NKG2D-CAR T cell-mediated anti-pancreatic cancer immunity by activating the JAK/STAT5 signaling pathway |
| title_full_unstemmed | Co-expression of IL-15/IL-15Ra complex enhances NKG2D-CAR T cell-mediated anti-pancreatic cancer immunity by activating the JAK/STAT5 signaling pathway |
| title_short | Co-expression of IL-15/IL-15Ra complex enhances NKG2D-CAR T cell-mediated anti-pancreatic cancer immunity by activating the JAK/STAT5 signaling pathway |
| title_sort | co expression of il 15 il 15ra complex enhances nkg2d car t cell mediated anti pancreatic cancer immunity by activating the jak stat5 signaling pathway |
| topic | NKG2D CAR T IL-15 pancreatic carcinoma JAK/STAT5 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1498706/full |
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