Antibody-based delivery of interleukin-2 modulates the immunosuppressive tumor microenvironment and achieves cure in pancreatic ductal adenocarcinoma syngeneic mice
Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadly type of cancer, with an extremely low five-year overall survival rate. To date, current treatment options primarily involve various chemotherapies, which often prove ineffective and are associated wi...
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BMC
2025-01-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-024-03238-x |
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| author | Carmine Carbone Roberto De Luca Emanuele Puca Antonio Agostini Alessia Caggiano Lorenzo Priori Annachiara Esposito Serena Ascrizzi Geny Piro Lisa Salvatore Francesco De Sanctis Stefano Ugel Vincenzo Corbo Dario Neri Giampaolo Tortora |
| author_facet | Carmine Carbone Roberto De Luca Emanuele Puca Antonio Agostini Alessia Caggiano Lorenzo Priori Annachiara Esposito Serena Ascrizzi Geny Piro Lisa Salvatore Francesco De Sanctis Stefano Ugel Vincenzo Corbo Dario Neri Giampaolo Tortora |
| author_sort | Carmine Carbone |
| collection | DOAJ |
| description | Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadly type of cancer, with an extremely low five-year overall survival rate. To date, current treatment options primarily involve various chemotherapies, which often prove ineffective and are associated with substantial toxicity. Furthermore, immunotherapies utilizing checkpoint inhibitors have shown limited efficacy in this context, highlighting an urgent need for novel therapeutic strategies. This study investigates the preclinical efficacy of an innovative targeted therapy based on antibody-cytokine fusion proteins, specifically interleukin-2 (IL-2), a pivotal driver of cell-mediated immunity, fused to L19 antibody, which selectively binds to extra domain B of fibronectin (EDB-FN1) expressed in the tumor microenvironment. Methods We tested the effectiveness of different immunocytokines through in vivo characterization in syngeneic C57BL/6J orthotopic mouse models of PDAC. Based on these results, we decided to focus on L19-IL2. To assess the efficacy of this immunocytokine we developed an ex-vivo immune-spheroid interaction platform derived from murine 3D pancreatic cultures, and telomerase reverse transcriptase (TERT) specific T-lymphocytes. Moreover, we evaluated the anti-cancer effect of L19-IL2 in combination with standard therapy in vivo experiments in PDAC mouse models. Tumor samples collected after the treatments were characterized for tumor infiltrating immune cell components by bulk RNA sequencing (RNA-seq) and spatial transcriptomics (Stereo-seq) analysis. Results The tumor-targeted L19-IL2 fusion protein demonstrated potent, dose-dependent anti-tumor activity in mice with pancreatic tumors resistant to standard chemotherapy. Spatial Transcriptomics (ST) and RNA-seq analyses indicated that L19-IL2 treatment induced a significant influx of immune cells into the tumor microenvironment, with these cells expressing activation markers like granzymes, perforins, and the IL-2 receptors. Conclusions Our results demonstrated that L19-IL2 enhances immune infiltration and cytotoxicity, remodeling the “cold” tumor microenvironment (TME) in PDAC. This innovative antibody-cytokine fusion protein improves therapeutic outcomes, paving the way for novel targeted treatment strategies in PDAC. |
| format | Article |
| id | doaj-art-1a2629d5cf774dee860ebe3926486953 |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-1a2629d5cf774dee860ebe39264869532025-01-12T12:44:40ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-01-0144111910.1186/s13046-024-03238-xAntibody-based delivery of interleukin-2 modulates the immunosuppressive tumor microenvironment and achieves cure in pancreatic ductal adenocarcinoma syngeneic miceCarmine Carbone0Roberto De Luca1Emanuele Puca2Antonio Agostini3Alessia Caggiano4Lorenzo Priori5Annachiara Esposito6Serena Ascrizzi7Geny Piro8Lisa Salvatore9Francesco De Sanctis10Stefano Ugel11Vincenzo Corbo12Dario Neri13Giampaolo Tortora14Department of Medical and Surgical Sciences, Medical Oncology , Fondazione Policlinico Universitario “Agostino Gemelli” IRCCSPhilochem AGPhilochem AGDepartment of Medical and Surgical Sciences, Medical Oncology , Fondazione Policlinico Universitario “Agostino Gemelli” IRCCSDepartment of Translational Medicine, Medical Oncology , Catholic University of the Sacred HeartDepartment of Translational Medicine, Medical Oncology , Catholic University of the Sacred HeartDepartment of Translational Medicine, Medical Oncology , Catholic University of the Sacred HeartDepartment of Translational Medicine, Medical Oncology , Catholic University of the Sacred HeartDepartment of Medical and Surgical Sciences, Medical Oncology , Fondazione Policlinico Universitario “Agostino Gemelli” IRCCSDepartment of Medical and Surgical Sciences, Medical Oncology , Fondazione Policlinico Universitario “Agostino Gemelli” IRCCSDepartment of Medicine, Section of Immunology, University of VeronaDepartment of Medicine, Section of Immunology, University of VeronaDepartment of Diagnostics and Public Health, University of VeronaDepartment of Chemistry and Applied Biosciences, Swiss Federal Institute of TechnologyDepartment of Medical and Surgical Sciences, Medical Oncology , Fondazione Policlinico Universitario “Agostino Gemelli” IRCCSAbstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadly type of cancer, with an extremely low five-year overall survival rate. To date, current treatment options primarily involve various chemotherapies, which often prove ineffective and are associated with substantial toxicity. Furthermore, immunotherapies utilizing checkpoint inhibitors have shown limited efficacy in this context, highlighting an urgent need for novel therapeutic strategies. This study investigates the preclinical efficacy of an innovative targeted therapy based on antibody-cytokine fusion proteins, specifically interleukin-2 (IL-2), a pivotal driver of cell-mediated immunity, fused to L19 antibody, which selectively binds to extra domain B of fibronectin (EDB-FN1) expressed in the tumor microenvironment. Methods We tested the effectiveness of different immunocytokines through in vivo characterization in syngeneic C57BL/6J orthotopic mouse models of PDAC. Based on these results, we decided to focus on L19-IL2. To assess the efficacy of this immunocytokine we developed an ex-vivo immune-spheroid interaction platform derived from murine 3D pancreatic cultures, and telomerase reverse transcriptase (TERT) specific T-lymphocytes. Moreover, we evaluated the anti-cancer effect of L19-IL2 in combination with standard therapy in vivo experiments in PDAC mouse models. Tumor samples collected after the treatments were characterized for tumor infiltrating immune cell components by bulk RNA sequencing (RNA-seq) and spatial transcriptomics (Stereo-seq) analysis. Results The tumor-targeted L19-IL2 fusion protein demonstrated potent, dose-dependent anti-tumor activity in mice with pancreatic tumors resistant to standard chemotherapy. Spatial Transcriptomics (ST) and RNA-seq analyses indicated that L19-IL2 treatment induced a significant influx of immune cells into the tumor microenvironment, with these cells expressing activation markers like granzymes, perforins, and the IL-2 receptors. Conclusions Our results demonstrated that L19-IL2 enhances immune infiltration and cytotoxicity, remodeling the “cold” tumor microenvironment (TME) in PDAC. This innovative antibody-cytokine fusion protein improves therapeutic outcomes, paving the way for novel targeted treatment strategies in PDAC.https://doi.org/10.1186/s13046-024-03238-xPancreatic cancerImmunocytokinesOrthotopic syngeneic mouse modelsChemotherapy |
| spellingShingle | Carmine Carbone Roberto De Luca Emanuele Puca Antonio Agostini Alessia Caggiano Lorenzo Priori Annachiara Esposito Serena Ascrizzi Geny Piro Lisa Salvatore Francesco De Sanctis Stefano Ugel Vincenzo Corbo Dario Neri Giampaolo Tortora Antibody-based delivery of interleukin-2 modulates the immunosuppressive tumor microenvironment and achieves cure in pancreatic ductal adenocarcinoma syngeneic mice Journal of Experimental & Clinical Cancer Research Pancreatic cancer Immunocytokines Orthotopic syngeneic mouse models Chemotherapy |
| title | Antibody-based delivery of interleukin-2 modulates the immunosuppressive tumor microenvironment and achieves cure in pancreatic ductal adenocarcinoma syngeneic mice |
| title_full | Antibody-based delivery of interleukin-2 modulates the immunosuppressive tumor microenvironment and achieves cure in pancreatic ductal adenocarcinoma syngeneic mice |
| title_fullStr | Antibody-based delivery of interleukin-2 modulates the immunosuppressive tumor microenvironment and achieves cure in pancreatic ductal adenocarcinoma syngeneic mice |
| title_full_unstemmed | Antibody-based delivery of interleukin-2 modulates the immunosuppressive tumor microenvironment and achieves cure in pancreatic ductal adenocarcinoma syngeneic mice |
| title_short | Antibody-based delivery of interleukin-2 modulates the immunosuppressive tumor microenvironment and achieves cure in pancreatic ductal adenocarcinoma syngeneic mice |
| title_sort | antibody based delivery of interleukin 2 modulates the immunosuppressive tumor microenvironment and achieves cure in pancreatic ductal adenocarcinoma syngeneic mice |
| topic | Pancreatic cancer Immunocytokines Orthotopic syngeneic mouse models Chemotherapy |
| url | https://doi.org/10.1186/s13046-024-03238-x |
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