Fibroblast activation protein targeted radiotherapy induces an immunogenic tumor microenvironment and enhances the efficacy of PD-1 immune checkpoint inhibition
| العنوان: | Fibroblast activation protein targeted radiotherapy induces an immunogenic tumor microenvironment and enhances the efficacy of PD-1 immune checkpoint inhibition |
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| المؤلفون: | Dirk Zboralski, Frank Osterkamp, Esben Christensen, Anne Bredenbeck, Anne Schumann, Aileen Hoehne, Eberhard Schneider, Matthias Paschke, Jan Ungewiss, Christian Haase, Liliane Robillard, Andrew D. Simmons, Thomas C. Harding, Minh Nguyen |
| المصدر: | European Journal of Nuclear Medicine and Molecular Imaging. |
| بيانات النشر: | Springer Science and Business Media LLC, 2023. |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | Radiology, Nuclear Medicine and imaging, General Medicine |
| الوصف: | Purpose FAP is a membrane-bound protease under investigation as a pan-cancer target, given its high levels in tumors but limited expression in normal tissues. FAP-2286 is a radiopharmaceutical in clinical development for solid tumors that consists of two functional elements: a FAP-targeting peptide and a chelator used to attach radioisotopes. Preclinically, we evaluated the immune modulation and anti-tumor efficacy of FAP-2287, a murine surrogate for FAP-2286, conjugated to the radionuclide lutetium-177 (177Lu) as a monotherapy and in combination with a PD-1 targeting antibody. Methods C57BL/6 mice bearing MCA205 mouse FAP-expressing tumors (MCA205-mFAP) were treated with 177Lu-FAP-2287, anti-PD-1, or both. Tumor uptake of 177Lu- FAP-2287 was assessed by SPECT/CT scanning, while therapeutic efficacy was measured by tumor volume and survival. Immune profiling of tumor infiltrates was evaluated through flow cytometry, RNA expression, and immunohistochemistry analyses. Results 177Lu-FAP-2287 rapidly accumulated in MCA205-mFAP tumors leading to significant tumor growth inhibition (TGI) and longer survival time. Significant TGI was also observed from anti-PD-1 and the combination. In flow cytometry analysis of tumors, 177Lu-FAP-2287 increased CD8+ T cell infiltration which was maintained in the combination with anti-PD-1. The increase in CD8+ T cells was accompanied by an induction of STING-mediated type I interferon response and higher levels of co-stimulatory molecules such as CD86. Conclusion In a preclinical model, FAP-targeted radiotherapy enhanced anti-PD-1-mediated TGI by modulating the TME and increasing the recruitment of tumor-infiltrating CD8+ T cells. These findings provide a rationale for clinical studies of combined 177Lu-FAP-2286 radiotherapy and immune checkpoint inhibition in FAP-positive tumors. |
| تدمد: | 1619-7089 1619-7070 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::cdd4a37db504ea8cc30fd8827c34bb4f https://doi.org/10.1007/s00259-023-06211-6 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi...........cdd4a37db504ea8cc30fd8827c34bb4f |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 16197089 16197070 |
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