4-1BB agonist targeted to fibroblast activation protein α synergizes with radiotherapy to treat murine breast tumor models
Background Ionizing radiation (IR) is a double-edged sword for immunotherapy as it may have both immunosuppressive and immunostimulatory effects. The biological effects of IR on the tumor microenvironment (TME) are a key factor for this balance. Fibroblast activation protein (FAP) is expressed on th...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2025-02-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/2/e009852.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823856595886407680 |
|---|---|
| author | Ignacio Melero Alvaro Teijeira Christian Klein Maria E Rodriguez-Ruiz Christina Claus Pablo Umana Tamara Tanos Carlos E De Andrea Carlos Luri-Rey Paloma Sanchez-Mateos Leticia Fernández-Rubio María Collantes Irantzu Serrano-Mendioroz Celia Barrio-Alonso Antonio Rullan Jon Ander Simon Eneko Garate-Soraluze Claudia del Pilar Herrero |
| author_facet | Ignacio Melero Alvaro Teijeira Christian Klein Maria E Rodriguez-Ruiz Christina Claus Pablo Umana Tamara Tanos Carlos E De Andrea Carlos Luri-Rey Paloma Sanchez-Mateos Leticia Fernández-Rubio María Collantes Irantzu Serrano-Mendioroz Celia Barrio-Alonso Antonio Rullan Jon Ander Simon Eneko Garate-Soraluze Claudia del Pilar Herrero |
| author_sort | Ignacio Melero |
| collection | DOAJ |
| description | Background Ionizing radiation (IR) is a double-edged sword for immunotherapy as it may have both immunosuppressive and immunostimulatory effects. The biological effects of IR on the tumor microenvironment (TME) are a key factor for this balance. Fibroblast activation protein (FAP) is expressed on the surface of cancer-associated fibroblasts (CAF) in many cancer types and its abundance is associated with the poor immune response to immune-checkpoint-blockade in patients. We hypothesized that IR increases FAP expression in CAFs, therefore the combination of IR with targeted immunomodulators such as an agonistic anti-FAP-4-1BBL fusion protein could enhance the immune-mediated antitumoral effects of these treatments.Methods The murine transplantable TS/A tumor-cell-line co-engrafted with CAFs was used to investigate increases in FAP expression in tumors following irradiation using immunohistochemistry, real-time polymerase chain reaction (RT-PCR) and multiplex tissue immunofluorescence. One lesion of bilateral tumor-bearing mice was only locally irradiated or combined with weekly injections of the bispecific muFAP-4-1BBL fusion protein (a mouse surrogate for RG7826). Tumor sizes were followed over time and TME was assessed by flow cytometry. Selective monoclonal antibody (mAb)-mediated depletions of immune cell populations, neutralizing interferon alpha/beta receptor 1 (IFNAR-I) IFNAR and interferon (IFN)-γ mAbs and gene-modified mice (4-1BB−/−) were used to delineate the immune cell subsets and mechanisms required for efficacy. 67Ga labeled muFAP-4-1BBL tracked by SPECT-CT was used to study biodistribution. In human colorectal carcinoma samples, the inducibility of FAP expression following radiotherapy was explored by multiplex immunofluorescence.Results Irradiation of TS/A+CAF tumors in mice showed an increase in FAP levels after local irradiation. A suboptimal radiotherapy regimen in combination with muFAP-4-1BBL attained primary tumor control and measurable abscopal effects. Immune TME landscape analyses showed post-treatment increased infiltration of activated immune cells associated with the combined radioimmunotherapy treatment. Efficacy depended on CD8+ T cells, type I IFN, IFN-γ and ability to express 4-1BB. Biodistribution studies of muFAP-4-1BBL indicated enriched tumor targeting to irradiated tumors. Human colorectal cancer samples pre and post irradiation showed enhanced FAP expression after radiotherapy.Conclusion Increased FAP expression in the TME as a result of radiotherapy can be exploited to target agonist 4-1BB immunotherapy to malignant tumor lesions using an FAP-4-1BBL antibody fusion protein. |
| format | Article |
| id | doaj-art-7b73e4bd587449c8859dc83c784fb64e |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-7b73e4bd587449c8859dc83c784fb64e2025-02-12T06:40:11ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-02-0113210.1136/jitc-2024-0098524-1BB agonist targeted to fibroblast activation protein α synergizes with radiotherapy to treat murine breast tumor modelsIgnacio Melero0Alvaro Teijeira1Christian Klein2Maria E Rodriguez-Ruiz3Christina Claus4Pablo Umana5Tamara Tanos6Carlos E De Andrea7Carlos Luri-Rey8Paloma Sanchez-Mateos9Leticia Fernández-Rubio10María Collantes11Irantzu Serrano-Mendioroz12Celia Barrio-Alonso13Antonio Rullan14Jon Ander Simon15Eneko Garate-Soraluze16Claudia del Pilar Herrero17Nuffield Department of Medicine, University of Oxford, Oxford, UKDepartment of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, SpainRoche Innovation Centre Zurich, Roche Pharma Research and Early Development (pRED), Schlieren, SwitzerlandDepartment of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, SpainRoche Innovation Centre Zurich, Roche Pharma Research and Early Development (pRED), Schlieren, SwitzerlandRoche Innovation Centre Zurich, Roche Pharma Research and Early Development (pRED), Schlieren, SwitzerlandRoche Innovation Centre Zurich, Roche Pharma Research and Early Development (pRED), Schlieren, SwitzerlandDepartment of Pathology, Cancer Center Clinica Universidad de Navarra, Pamplona, SpainDepartment of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, SpainDepartment of Immunology, Hospital Gregorio Marañon, Madrid, Madrid, SpainDepartment of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, SpainDepartment of Nuclear Medicine, Clinica Universidad de Navarra, Pamplona, SpainDepartment of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, SpainDepartment of Immunology, Hospital Gregorio Marañon, Madrid, Madrid, SpainInstitute of Immunology and Transplantation, University College London, London, UKDepartment of Nuclear Medicine, Clinica Universidad de Navarra, Pamplona, SpainDepartment of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, SpainDepartment of Pathology, Cancer Center Clinica Universidad de Navarra, Pamplona, SpainBackground Ionizing radiation (IR) is a double-edged sword for immunotherapy as it may have both immunosuppressive and immunostimulatory effects. The biological effects of IR on the tumor microenvironment (TME) are a key factor for this balance. Fibroblast activation protein (FAP) is expressed on the surface of cancer-associated fibroblasts (CAF) in many cancer types and its abundance is associated with the poor immune response to immune-checkpoint-blockade in patients. We hypothesized that IR increases FAP expression in CAFs, therefore the combination of IR with targeted immunomodulators such as an agonistic anti-FAP-4-1BBL fusion protein could enhance the immune-mediated antitumoral effects of these treatments.Methods The murine transplantable TS/A tumor-cell-line co-engrafted with CAFs was used to investigate increases in FAP expression in tumors following irradiation using immunohistochemistry, real-time polymerase chain reaction (RT-PCR) and multiplex tissue immunofluorescence. One lesion of bilateral tumor-bearing mice was only locally irradiated or combined with weekly injections of the bispecific muFAP-4-1BBL fusion protein (a mouse surrogate for RG7826). Tumor sizes were followed over time and TME was assessed by flow cytometry. Selective monoclonal antibody (mAb)-mediated depletions of immune cell populations, neutralizing interferon alpha/beta receptor 1 (IFNAR-I) IFNAR and interferon (IFN)-γ mAbs and gene-modified mice (4-1BB−/−) were used to delineate the immune cell subsets and mechanisms required for efficacy. 67Ga labeled muFAP-4-1BBL tracked by SPECT-CT was used to study biodistribution. In human colorectal carcinoma samples, the inducibility of FAP expression following radiotherapy was explored by multiplex immunofluorescence.Results Irradiation of TS/A+CAF tumors in mice showed an increase in FAP levels after local irradiation. A suboptimal radiotherapy regimen in combination with muFAP-4-1BBL attained primary tumor control and measurable abscopal effects. Immune TME landscape analyses showed post-treatment increased infiltration of activated immune cells associated with the combined radioimmunotherapy treatment. Efficacy depended on CD8+ T cells, type I IFN, IFN-γ and ability to express 4-1BB. Biodistribution studies of muFAP-4-1BBL indicated enriched tumor targeting to irradiated tumors. Human colorectal cancer samples pre and post irradiation showed enhanced FAP expression after radiotherapy.Conclusion Increased FAP expression in the TME as a result of radiotherapy can be exploited to target agonist 4-1BB immunotherapy to malignant tumor lesions using an FAP-4-1BBL antibody fusion protein.https://jitc.bmj.com/content/13/2/e009852.full |
| spellingShingle | Ignacio Melero Alvaro Teijeira Christian Klein Maria E Rodriguez-Ruiz Christina Claus Pablo Umana Tamara Tanos Carlos E De Andrea Carlos Luri-Rey Paloma Sanchez-Mateos Leticia Fernández-Rubio María Collantes Irantzu Serrano-Mendioroz Celia Barrio-Alonso Antonio Rullan Jon Ander Simon Eneko Garate-Soraluze Claudia del Pilar Herrero 4-1BB agonist targeted to fibroblast activation protein α synergizes with radiotherapy to treat murine breast tumor models Journal for ImmunoTherapy of Cancer |
| title | 4-1BB agonist targeted to fibroblast activation protein α synergizes with radiotherapy to treat murine breast tumor models |
| title_full | 4-1BB agonist targeted to fibroblast activation protein α synergizes with radiotherapy to treat murine breast tumor models |
| title_fullStr | 4-1BB agonist targeted to fibroblast activation protein α synergizes with radiotherapy to treat murine breast tumor models |
| title_full_unstemmed | 4-1BB agonist targeted to fibroblast activation protein α synergizes with radiotherapy to treat murine breast tumor models |
| title_short | 4-1BB agonist targeted to fibroblast activation protein α synergizes with radiotherapy to treat murine breast tumor models |
| title_sort | 4 1bb agonist targeted to fibroblast activation protein α synergizes with radiotherapy to treat murine breast tumor models |
| url | https://jitc.bmj.com/content/13/2/e009852.full |
| work_keys_str_mv | AT ignaciomelero 41bbagonisttargetedtofibroblastactivationproteinasynergizeswithradiotherapytotreatmurinebreasttumormodels AT alvaroteijeira 41bbagonisttargetedtofibroblastactivationproteinasynergizeswithradiotherapytotreatmurinebreasttumormodels AT christianklein 41bbagonisttargetedtofibroblastactivationproteinasynergizeswithradiotherapytotreatmurinebreasttumormodels AT mariaerodriguezruiz 41bbagonisttargetedtofibroblastactivationproteinasynergizeswithradiotherapytotreatmurinebreasttumormodels AT christinaclaus 41bbagonisttargetedtofibroblastactivationproteinasynergizeswithradiotherapytotreatmurinebreasttumormodels AT pabloumana 41bbagonisttargetedtofibroblastactivationproteinasynergizeswithradiotherapytotreatmurinebreasttumormodels AT tamaratanos 41bbagonisttargetedtofibroblastactivationproteinasynergizeswithradiotherapytotreatmurinebreasttumormodels AT carlosedeandrea 41bbagonisttargetedtofibroblastactivationproteinasynergizeswithradiotherapytotreatmurinebreasttumormodels AT carloslurirey 41bbagonisttargetedtofibroblastactivationproteinasynergizeswithradiotherapytotreatmurinebreasttumormodels AT palomasanchezmateos 41bbagonisttargetedtofibroblastactivationproteinasynergizeswithradiotherapytotreatmurinebreasttumormodels AT leticiafernandezrubio 41bbagonisttargetedtofibroblastactivationproteinasynergizeswithradiotherapytotreatmurinebreasttumormodels AT mariacollantes 41bbagonisttargetedtofibroblastactivationproteinasynergizeswithradiotherapytotreatmurinebreasttumormodels AT irantzuserranomendioroz 41bbagonisttargetedtofibroblastactivationproteinasynergizeswithradiotherapytotreatmurinebreasttumormodels AT celiabarrioalonso 41bbagonisttargetedtofibroblastactivationproteinasynergizeswithradiotherapytotreatmurinebreasttumormodels AT antoniorullan 41bbagonisttargetedtofibroblastactivationproteinasynergizeswithradiotherapytotreatmurinebreasttumormodels AT jonandersimon 41bbagonisttargetedtofibroblastactivationproteinasynergizeswithradiotherapytotreatmurinebreasttumormodels AT enekogaratesoraluze 41bbagonisttargetedtofibroblastactivationproteinasynergizeswithradiotherapytotreatmurinebreasttumormodels AT claudiadelpilarherrero 41bbagonisttargetedtofibroblastactivationproteinasynergizeswithradiotherapytotreatmurinebreasttumormodels |