{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:28:18Z","timestamp":1792787298277,"version":"4.5.0"},"reference-count":55,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T00:00:00Z","timestamp":1739232000000},"content-version":"unspecified","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100023479","name":"CRIS Cancer Foundation","doi-asserted-by":"publisher","award":["PR_TCL_2020-3"],"award-info":[{"award-number":["PR_TCL_2020-3"]}],"id":[{"id":"10.13039\/501100023479","id-type":"DOI","asserted-by":"publisher"}]},{"name":"imCORE Network on behalf of F. Hoffmann-La Roche","award":["NAV-11 project"],"award-info":[{"award-number":["NAV-11 project"]}]},{"DOI":"10.13039\/501100002704","name":"Fundaci\u00f3n Cient\u00edfica Asociaci\u00f3n Espa\u00f1ola Contra el C\u00e1ncer","doi-asserted-by":"publisher","award":["PRDNA234014GARA"],"award-info":[{"award-number":["PRDNA234014GARA"]}],"id":[{"id":"10.13039\/501100002704","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2024,11,1]]},"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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)-\u03b3 mAbs and gene-modified mice (4-1BB\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      ) were used to delineate the immune cell subsets and mechanisms required for efficacy.\n                      <jats:sup>67<\/jats:sup>\n                      Ga 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:sup>+<\/jats:sup>\n                      T cells, type I IFN, IFN-\u03b3 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2024-009852","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T12:50:53Z","timestamp":1739278253000},"page":"e009852","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":20,"title":["4-1BB agonist targeted to fibroblast activation protein \u03b1 synergizes with radiotherapy to treat murine breast tumor 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