Pre-existing TGF-β-specific T-cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapy
Background Circulating transforming growth factor-β (TGF-β)-specific T cells that recognize TGF-β-expressing immune regulatory cells have been described in patients with cancer. TGF-β-derived peptide vaccination modulates the tumor microenvironment and has shown clinical effects in animal models of...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/3/e006432.full |
| _version_ | 1827890009137479680 |
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| author | Mads Hald Andersen Özcan Met Inge Marie Svane Morten Orebo Holmström Thomas Landkildehus Lisle Rasmus Erik Johansson Mortensen Jane P Hasselby Gro L Willemoe Julia Johansen Dorte L Nielsen Inna M Chen |
| author_facet | Mads Hald Andersen Özcan Met Inge Marie Svane Morten Orebo Holmström Thomas Landkildehus Lisle Rasmus Erik Johansson Mortensen Jane P Hasselby Gro L Willemoe Julia Johansen Dorte L Nielsen Inna M Chen |
| author_sort | Mads Hald Andersen |
| collection | DOAJ |
| description | Background Circulating transforming growth factor-β (TGF-β)-specific T cells that recognize TGF-β-expressing immune regulatory cells have been described in patients with cancer. TGF-β-derived peptide vaccination modulates the tumor microenvironment and has shown clinical effects in animal models of pancreatic cancer (PC). TGF-β-expressing regulatory cells are especially elevated in PC and may prevent the clinical response to immune checkpoint inhibitors (ICIs). Thus, in the present study we investigated the significance of TGF-β-specific T-cell immunity in patients with PC treated with ICI combined with radiotherapy in a randomized phase 2 study (CheckPAC).Methods Immune responses to a TGF-β-derived epitope entitled TGF-β-15 as well as epitopes from Clostridium tetani (tetanus) and influenza were measured in peripheral blood mononuclear cells (PBMCs) with interferon-ɣ enzyme-linked immunospot assays. PBMCs were isolated before and after treatment. Correlations between immune response data and clinical data were evaluated with parametric and non-parametric statistical methods. Survival was analyzed with univariate and multivariate Cox-regression. TGF-β-15 specific T cells were isolated and expanded and examined for recognition of autologous regulatory immune cells by flow cytometry.Results PBMCs from 32 patients were analyzed for immune responses to the TGF-β-derived epitope entitled TGF-β-15. Patients with a strong TGF-β-specific immune response at treatment initiation had longer progression-free and overall survival, compared with patients with a weak or no TGF-β-specific immune response. This remained significant in multivariate analysis. Patients with weak and strong TGF-β-specific responses displayed similar responses towards viral antigens. Furthermore, we show that TGF-β-specific T cells from a clinical responder specifically reacted to and lysed autologous, regulatory immune cells. Finally, mimicking a TGF-β-15 vaccination, we showed that repeated stimulations with the TGF-β-15 epitope in vitro enhanced the immune response to TGF-β-15.Conclusion A strong TGF-β-15 specific immune response was associated with clinical benefit and improved survival after ICI/radiotherapy for patients with PC. Importantly, the lack of TGF-β-specific T cells in some patients was not caused by a general immune dysfunction. TGF-β-specific T cells recognized regulatory immune cells and could be introduced in vitro in patients without spontaneous responses. Taken together, our data suggest that combining TGF-β-based vaccination with ICI/radiotherapy will be beneficial for patients with PC. |
| first_indexed | 2024-03-12T21:04:05Z |
| format | Article |
| id | doaj.art-86495d8680aa4a59a67aa19a352593ff |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-12T21:04:05Z |
| publishDate | 2023-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-86495d8680aa4a59a67aa19a352593ff2023-07-30T15:35:06ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-03-0111310.1136/jitc-2022-006432Pre-existing TGF-β-specific T-cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapyMads Hald Andersen0Özcan Met1Inge Marie Svane2Morten Orebo Holmström3Thomas Landkildehus Lisle4Rasmus Erik Johansson Mortensen5Jane P Hasselby6Gro L Willemoe7Julia Johansen8Dorte L Nielsen9Inna M Chen10Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, DenmarkNational Center for Cancer Immune Therapy, Department of Oncology, Herlev Hospital, Herlev, DenmarkNational Center for Cancer Immune Therapy, Department of Oncology, Herlev Hospital, Herlev, DenmarkNational Center for Cancer Immune Therapy, Department of Oncology, Herlev Hospital, Herlev, DenmarkNational Center for Cancer Immune Therapy, Department of Oncology, Herlev Hospital, Herlev, DenmarkNational Center for Cancer Immune Therapy, Department of Oncology, Herlev Hospital, Herlev, DenmarkDepartment of Pathology, Rigshospitalet, Copenhagen, DenmarkDepartment of Pathology, Rigshospitalet, Copenhagen, DenmarkDepartment of Oncology, Herlev Hospital, Herlev, DenmarkDepartment of Oncology, Herlev Hospital, Herlev, DenmarkDepartment of Oncology, Herlev Hospital, Herlev, DenmarkBackground Circulating transforming growth factor-β (TGF-β)-specific T cells that recognize TGF-β-expressing immune regulatory cells have been described in patients with cancer. TGF-β-derived peptide vaccination modulates the tumor microenvironment and has shown clinical effects in animal models of pancreatic cancer (PC). TGF-β-expressing regulatory cells are especially elevated in PC and may prevent the clinical response to immune checkpoint inhibitors (ICIs). Thus, in the present study we investigated the significance of TGF-β-specific T-cell immunity in patients with PC treated with ICI combined with radiotherapy in a randomized phase 2 study (CheckPAC).Methods Immune responses to a TGF-β-derived epitope entitled TGF-β-15 as well as epitopes from Clostridium tetani (tetanus) and influenza were measured in peripheral blood mononuclear cells (PBMCs) with interferon-ɣ enzyme-linked immunospot assays. PBMCs were isolated before and after treatment. Correlations between immune response data and clinical data were evaluated with parametric and non-parametric statistical methods. Survival was analyzed with univariate and multivariate Cox-regression. TGF-β-15 specific T cells were isolated and expanded and examined for recognition of autologous regulatory immune cells by flow cytometry.Results PBMCs from 32 patients were analyzed for immune responses to the TGF-β-derived epitope entitled TGF-β-15. Patients with a strong TGF-β-specific immune response at treatment initiation had longer progression-free and overall survival, compared with patients with a weak or no TGF-β-specific immune response. This remained significant in multivariate analysis. Patients with weak and strong TGF-β-specific responses displayed similar responses towards viral antigens. Furthermore, we show that TGF-β-specific T cells from a clinical responder specifically reacted to and lysed autologous, regulatory immune cells. Finally, mimicking a TGF-β-15 vaccination, we showed that repeated stimulations with the TGF-β-15 epitope in vitro enhanced the immune response to TGF-β-15.Conclusion A strong TGF-β-15 specific immune response was associated with clinical benefit and improved survival after ICI/radiotherapy for patients with PC. Importantly, the lack of TGF-β-specific T cells in some patients was not caused by a general immune dysfunction. TGF-β-specific T cells recognized regulatory immune cells and could be introduced in vitro in patients without spontaneous responses. Taken together, our data suggest that combining TGF-β-based vaccination with ICI/radiotherapy will be beneficial for patients with PC.https://jitc.bmj.com/content/11/3/e006432.full |
| spellingShingle | Mads Hald Andersen Özcan Met Inge Marie Svane Morten Orebo Holmström Thomas Landkildehus Lisle Rasmus Erik Johansson Mortensen Jane P Hasselby Gro L Willemoe Julia Johansen Dorte L Nielsen Inna M Chen Pre-existing TGF-β-specific T-cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapy Journal for ImmunoTherapy of Cancer |
| title | Pre-existing TGF-β-specific T-cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapy |
| title_full | Pre-existing TGF-β-specific T-cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapy |
| title_fullStr | Pre-existing TGF-β-specific T-cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapy |
| title_full_unstemmed | Pre-existing TGF-β-specific T-cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapy |
| title_short | Pre-existing TGF-β-specific T-cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapy |
| title_sort | pre existing tgf β specific t cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapy |
| url | https://jitc.bmj.com/content/11/3/e006432.full |
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