TNFR2 blockade promotes antitumoral immune response in PDAC by targeting activated Treg and reducing T cell exhaustion
Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, highly resistant to standard chemotherapy and immunotherapy. Regulatory T cells (Tregs) expressing tumor necrosis factor α receptor 2 (TNFR2) contribute to immunosuppression in PDAC. Treg infiltration correlate...
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BMJ Publishing Group
2024-11-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/11/e008898.full |
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| author | Eliane Piaggio Allan Thiolat Anais Debesset Caroline Pilon Benoît Laurent Salomon José Laurent Cohen Sylvain Baulande Sylvain Meunier Orianne Cuelenaere-Bonizec Wilfrid Richer Claire Houppe Matteo Ponzo Jeanne Magnan Jonathan Caron Pamela Caudana Jimena Tosello Boari Nhu Han To Ilaria Cascone |
| author_facet | Eliane Piaggio Allan Thiolat Anais Debesset Caroline Pilon Benoît Laurent Salomon José Laurent Cohen Sylvain Baulande Sylvain Meunier Orianne Cuelenaere-Bonizec Wilfrid Richer Claire Houppe Matteo Ponzo Jeanne Magnan Jonathan Caron Pamela Caudana Jimena Tosello Boari Nhu Han To Ilaria Cascone |
| author_sort | Eliane Piaggio |
| collection | DOAJ |
| description | Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, highly resistant to standard chemotherapy and immunotherapy. Regulatory T cells (Tregs) expressing tumor necrosis factor α receptor 2 (TNFR2) contribute to immunosuppression in PDAC. Treg infiltration correlates with poor survival and tumor progression in patients with PDAC. We hypothesized that TNFR2 inhibition using a blocking monoclonal antibody (mAb) could shift the Treg-effector T cell balance in PDAC, thus enhancing antitumoral responses.Method To support this hypothesis, we first described TNFR2 expression in a cohort of 24 patients with PDAC from publicly available single-cell analysis data. In orthotopic and immunocompetent mouse models of PDAC, we also described the immune environment of PDAC after immune cell sorting and single-cell analysis. The modifications of the immune environment before and after anti-TNFR2 mAb treatment were evaluated as well as the effect on tumor progression.Results Patients with PDAC exhibited elevated TNFR2 expression in Treg, myeloid cells and endothelial cells and lower level in tumor cells. By flow cytometry and single-cell RNA-seq analysis, we identified two Treg populations in orthotopic mouse models: Resting and activated Tregs. The anti-TNFR2 mAb selectively targeted activated tumor-infiltrating Tregs, reducing T cell exhaustion markers in CD8+ T cells. However, anti-TNFR2 treatment alone had limited efficacy in activating CD8+ T cells and only slightly reduced the tumor growth. The combination of the anti-TNFR2 mAb with agonistic anti-CD40 mAb promoted stronger T cell activation, tumor growth inhibition, and improved survival and immunological memory in PDAC-bearing mice.Conclusion Our data suggest that combining a CD40 agonist with a TNFR2 antagonist represents a promising therapeutic strategy for patients with PDAC. |
| format | Article |
| id | doaj-art-3f68bef7704c46289269850f3be85bc5 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-3f68bef7704c46289269850f3be85bc52024-11-25T18:00:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-11-01121110.1136/jitc-2024-008898TNFR2 blockade promotes antitumoral immune response in PDAC by targeting activated Treg and reducing T cell exhaustionEliane Piaggio0Allan Thiolat1Anais Debesset2Caroline Pilon3Benoît Laurent Salomon4José Laurent Cohen5Sylvain Baulande6Sylvain Meunier7Orianne Cuelenaere-Bonizec8Wilfrid Richer9Claire Houppe10Matteo Ponzo11Jeanne Magnan12Jonathan Caron13Pamela Caudana14Jimena Tosello Boari15Nhu Han To16Ilaria Cascone17Department of Translational Research, Institut Curie Research center, PSL Research University, Paris, FranceINSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, FranceINSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, FranceINSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, FranceToulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291, CNRS UMR5051, University Toulouse III, Toulouse, FranceINSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, FranceInstitut Curie Research Center, ICGex Next-Generation Sequencing Platform, Single Cell Initiative, PSL Research University, Paris, FranceINSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, FranceINSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, FranceINSERM U932, Institute Curie Research Center, PSL Research University, Paris, FranceINSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, FranceINSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, FranceINSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, FranceINSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, FranceINSERM U932, Institute Curie Research Center, PSL Research University, Paris, FranceINSERM U932, Institute Curie Research Center, PSL Research University, Paris, FranceINSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, FranceINSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, FranceBackground Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, highly resistant to standard chemotherapy and immunotherapy. Regulatory T cells (Tregs) expressing tumor necrosis factor α receptor 2 (TNFR2) contribute to immunosuppression in PDAC. Treg infiltration correlates with poor survival and tumor progression in patients with PDAC. We hypothesized that TNFR2 inhibition using a blocking monoclonal antibody (mAb) could shift the Treg-effector T cell balance in PDAC, thus enhancing antitumoral responses.Method To support this hypothesis, we first described TNFR2 expression in a cohort of 24 patients with PDAC from publicly available single-cell analysis data. In orthotopic and immunocompetent mouse models of PDAC, we also described the immune environment of PDAC after immune cell sorting and single-cell analysis. The modifications of the immune environment before and after anti-TNFR2 mAb treatment were evaluated as well as the effect on tumor progression.Results Patients with PDAC exhibited elevated TNFR2 expression in Treg, myeloid cells and endothelial cells and lower level in tumor cells. By flow cytometry and single-cell RNA-seq analysis, we identified two Treg populations in orthotopic mouse models: Resting and activated Tregs. The anti-TNFR2 mAb selectively targeted activated tumor-infiltrating Tregs, reducing T cell exhaustion markers in CD8+ T cells. However, anti-TNFR2 treatment alone had limited efficacy in activating CD8+ T cells and only slightly reduced the tumor growth. The combination of the anti-TNFR2 mAb with agonistic anti-CD40 mAb promoted stronger T cell activation, tumor growth inhibition, and improved survival and immunological memory in PDAC-bearing mice.Conclusion Our data suggest that combining a CD40 agonist with a TNFR2 antagonist represents a promising therapeutic strategy for patients with PDAC.https://jitc.bmj.com/content/12/11/e008898.full |
| spellingShingle | Eliane Piaggio Allan Thiolat Anais Debesset Caroline Pilon Benoît Laurent Salomon José Laurent Cohen Sylvain Baulande Sylvain Meunier Orianne Cuelenaere-Bonizec Wilfrid Richer Claire Houppe Matteo Ponzo Jeanne Magnan Jonathan Caron Pamela Caudana Jimena Tosello Boari Nhu Han To Ilaria Cascone TNFR2 blockade promotes antitumoral immune response in PDAC by targeting activated Treg and reducing T cell exhaustion Journal for ImmunoTherapy of Cancer |
| title | TNFR2 blockade promotes antitumoral immune response in PDAC by targeting activated Treg and reducing T cell exhaustion |
| title_full | TNFR2 blockade promotes antitumoral immune response in PDAC by targeting activated Treg and reducing T cell exhaustion |
| title_fullStr | TNFR2 blockade promotes antitumoral immune response in PDAC by targeting activated Treg and reducing T cell exhaustion |
| title_full_unstemmed | TNFR2 blockade promotes antitumoral immune response in PDAC by targeting activated Treg and reducing T cell exhaustion |
| title_short | TNFR2 blockade promotes antitumoral immune response in PDAC by targeting activated Treg and reducing T cell exhaustion |
| title_sort | tnfr2 blockade promotes antitumoral immune response in pdac by targeting activated treg and reducing t cell exhaustion |
| url | https://jitc.bmj.com/content/12/11/e008898.full |
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