c-Met<sup>+</sup> Cytotoxic T Lymphocytes Exhibit Enhanced Cytotoxicity in Mice and Humans In Vitro Tumor Models
CD8<sup>+</sup> cytotoxic T lymphocytes (CTLs) play a crucial role in anti-tumor immunity. In a previous study, we identified a subset of murine effector CTLs expressing the hepatocyte growth factor (HGF) receptor, c-Met (c-Met<sup>+</sup> CTLs), that are endowed with enhance...
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MDPI AG
2023-11-01
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| Online Access: | https://www.mdpi.com/2227-9059/11/12/3123 |
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| author | Mahdia Benkhoucha Ngoc Lan Tran Isis Senoner Gautier Breville Hajer Fritah Denis Migliorini Valérie Dutoit Patrice H. Lalive |
| author_facet | Mahdia Benkhoucha Ngoc Lan Tran Isis Senoner Gautier Breville Hajer Fritah Denis Migliorini Valérie Dutoit Patrice H. Lalive |
| author_sort | Mahdia Benkhoucha |
| collection | DOAJ |
| description | CD8<sup>+</sup> cytotoxic T lymphocytes (CTLs) play a crucial role in anti-tumor immunity. In a previous study, we identified a subset of murine effector CTLs expressing the hepatocyte growth factor (HGF) receptor, c-Met (c-Met<sup>+</sup> CTLs), that are endowed with enhanced cytolytic capacity. HGF directly inhibited the cytolytic function of c-Met<sup>+</sup> CTLs, both in 2D in vitro assays and in vivo, leading to reduced T cell responses against metastatic melanoma. To further investigate the role of c-Met<sup>+</sup> CTLs in a three-dimensional (3D) setting, we studied their function within B16 melanoma spheroids and examined the impact of cell–cell contact on the modulation of inhibitory checkpoint molecules’ expression, such as KLRG1, PD-1, and CTLA-4. Additionally, we evaluated the cytolytic capacity of human CTL clones expressing c-Met (c-Met<sup>+</sup>) and compared it to c-Met<sup>−</sup> CTL clones. Our results indicated that, similar to their murine counterparts, c-Met<sup>+</sup> human CTL clones exhibited increased cytolytic activity compared to c-Met<sup>−</sup> CTL clones, and this enhanced function was negatively regulated by the presence of HGF. Taken together, our findings highlight the potential of targeting the HGF/c-Met pathway to modulate CTL-mediated anti-tumor immunity. This research holds promise for developing strategies to enhance the effectiveness of CTL-based immunotherapies against cancer. |
| first_indexed | 2024-03-08T20:58:43Z |
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| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-08T20:58:43Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-7fca482d6bb04fd4aac99339b05ae8592023-12-22T13:54:43ZengMDPI AGBiomedicines2227-90592023-11-011112312310.3390/biomedicines11123123c-Met<sup>+</sup> Cytotoxic T Lymphocytes Exhibit Enhanced Cytotoxicity in Mice and Humans In Vitro Tumor ModelsMahdia Benkhoucha0Ngoc Lan Tran1Isis Senoner2Gautier Breville3Hajer Fritah4Denis Migliorini5Valérie Dutoit6Patrice H. Lalive7Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, SwitzerlandDepartment of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, SwitzerlandDepartment of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, SwitzerlandDepartment of Clinical Neurosciences, Division of Neurology, University Hospital of Geneva, 1205 Geneva, SwitzerlandDepartment of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, SwitzerlandBrain Tumor and Immune Cell Engineering Laboratory, Department of Medicine, Faculty of Medicine, University of Geneva, 1211 Geneva, SwitzerlandBrain Tumor and Immune Cell Engineering Laboratory, Department of Medicine, Faculty of Medicine, University of Geneva, 1211 Geneva, SwitzerlandDepartment of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, SwitzerlandCD8<sup>+</sup> cytotoxic T lymphocytes (CTLs) play a crucial role in anti-tumor immunity. In a previous study, we identified a subset of murine effector CTLs expressing the hepatocyte growth factor (HGF) receptor, c-Met (c-Met<sup>+</sup> CTLs), that are endowed with enhanced cytolytic capacity. HGF directly inhibited the cytolytic function of c-Met<sup>+</sup> CTLs, both in 2D in vitro assays and in vivo, leading to reduced T cell responses against metastatic melanoma. To further investigate the role of c-Met<sup>+</sup> CTLs in a three-dimensional (3D) setting, we studied their function within B16 melanoma spheroids and examined the impact of cell–cell contact on the modulation of inhibitory checkpoint molecules’ expression, such as KLRG1, PD-1, and CTLA-4. Additionally, we evaluated the cytolytic capacity of human CTL clones expressing c-Met (c-Met<sup>+</sup>) and compared it to c-Met<sup>−</sup> CTL clones. Our results indicated that, similar to their murine counterparts, c-Met<sup>+</sup> human CTL clones exhibited increased cytolytic activity compared to c-Met<sup>−</sup> CTL clones, and this enhanced function was negatively regulated by the presence of HGF. Taken together, our findings highlight the potential of targeting the HGF/c-Met pathway to modulate CTL-mediated anti-tumor immunity. This research holds promise for developing strategies to enhance the effectiveness of CTL-based immunotherapies against cancer.https://www.mdpi.com/2227-9059/11/12/3123c-MetHGFCTLsCD8<sup>+</sup> cytotoxic T lymphocytesspheroidstumor |
| spellingShingle | Mahdia Benkhoucha Ngoc Lan Tran Isis Senoner Gautier Breville Hajer Fritah Denis Migliorini Valérie Dutoit Patrice H. Lalive c-Met<sup>+</sup> Cytotoxic T Lymphocytes Exhibit Enhanced Cytotoxicity in Mice and Humans In Vitro Tumor Models Biomedicines c-Met HGF CTLs CD8<sup>+</sup> cytotoxic T lymphocytes spheroids tumor |
| title | c-Met<sup>+</sup> Cytotoxic T Lymphocytes Exhibit Enhanced Cytotoxicity in Mice and Humans In Vitro Tumor Models |
| title_full | c-Met<sup>+</sup> Cytotoxic T Lymphocytes Exhibit Enhanced Cytotoxicity in Mice and Humans In Vitro Tumor Models |
| title_fullStr | c-Met<sup>+</sup> Cytotoxic T Lymphocytes Exhibit Enhanced Cytotoxicity in Mice and Humans In Vitro Tumor Models |
| title_full_unstemmed | c-Met<sup>+</sup> Cytotoxic T Lymphocytes Exhibit Enhanced Cytotoxicity in Mice and Humans In Vitro Tumor Models |
| title_short | c-Met<sup>+</sup> Cytotoxic T Lymphocytes Exhibit Enhanced Cytotoxicity in Mice and Humans In Vitro Tumor Models |
| title_sort | c met sup sup cytotoxic t lymphocytes exhibit enhanced cytotoxicity in mice and humans in vitro tumor models |
| topic | c-Met HGF CTLs CD8<sup>+</sup> cytotoxic T lymphocytes spheroids tumor |
| url | https://www.mdpi.com/2227-9059/11/12/3123 |
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