FAP-targeted radioligand therapy with (68)Ga/(177)Lu-DOTA-2P(FAPI)(2) enhance immunogenicity and synergize with PD-L1 inhibitors for improved antitumor efficacy
(1) Chen J (2) Zhou Y (3) Pang Y (4) Fu K (5) Luo Q (6) Sun L (7) Wu H (8) Lin Q (9) Su G (10) Chen X (11) Zhao L (12) Chen H
BACKGROUND: Fibroblast activation protein (FAP)-targeted radioligand therapy, with immunomodulatory effects, has shown efficacy in both preclinical and clinical studies. We recently reported on a novel dimeric FAP-targeting radiopharmaceutical, (68)Ga/(177)Lu-DOTA-2P(FAPI)(2), which demonstrated increased tumor uptake and prolonged retention in various cancers. However, further exploration is required to understand the therapeutic efficacy and underlying mechanisms of combining (68)Ga/(177)Lu-DOTA-2P(FAPI)(2) radioligand therapy with PD-1/PD-L1 immunotherapy. METHODS: Regarding the change in PD-L1 expression and DNA double-strand breaks induced by radiopharmaceuticals, CT26-FAP tumor cells were incubated with (68)Ga and (177)Lu labeled DOTA-2P(FAPI)(2), respectively. Monotherapy with (68)Ga-DOTA-2P(FAPI)(2), (177)Lu-DOTA-2P(FAPI)(2), and PD-L1 immunotherapy as well as combination therapy ((68)Ga/(177)Lu-DOTA-2P(FAPI)(2) and PD-L1 immunotherapy) were tested and evaluated to evaluate in vivo antitumor efficacy. Furthermore, immunohistochemical staining and single-cell RNA sequencing were used to analyze changes in the tumor microenvironment (TME) and elucidate the underlying mechanisms of action of this combination therapy. RESULTS: Our findings indicated that FAP-targeting radiopharmaceuticals can induce DNA double-strand breaks and upregulate PD-L1 expression, with (177)Lu-DOTA-2P(FAPI)(2) proving to be more effective than (68)Ga-DOTA-2P(FAPI)(2). Both (68)Ga-DOTA-2P(FAPI)(2) and (177)Lu-DOTA-2P(FAPI)(2) radiopharmaceuticals significantly improved therapeutic outcomes when combined with anti-PD-L1 monoclonal antibody (_PD-L1 mAb). Notably, the combination of (177)Lu-DOTA-2P(FAPI)(2) with _PD-L1 mAb immunotherapy eliminated tumors in mouse models. Mice treated with this regimen not only exhibited exceptional responses to the initial immune checkpoint inhibitor therapy but also showed 100% tumor rejection on subsequent tumor cell re-inoculation. Further mechanistic studies have shown that (177)Lu-DOTA-2P(FAPI)(2) combined with _PD-L1 mAb can reprogram the TME, enhancing antitumor intercellular communication, which activates antitumor-related intercellular contacts such as FasL-Fas interactions between T cells and NK cells with tumor cells and increasing the proportion of infiltrating CD8+ T-cells while reducing regulatory T cells and inhibiting tumor progression. Our research also demonstrates that mature neutrophils play a role in enhancing the efficacy of the combined therapy, as shown in neutrophil-blocking experiments. CONCLUSIONS: Our study robustly advocates for use of FAP-targeting radiopharmaceuticals, particularly (177)Lu-DOTA-2P(FAPI)(2), alongside immunotherapy in treating FAP-positive tumors. This combination therapy transforms the TME and enables a translatable approach to increasing the sensitivity to PD-1/PD-L1 immunotherapy, leading to improved complete remission rates and extended overall survival.
Author Info:
(1) Department of Nuclear Medicine and Minnan PET Center, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, F
ujian, China. Department of Colorectal Tumor Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China. (2) Department of Nuclear Medicine and Minnan PET Center, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China. Department of Radiation Oncology, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China. (3) Department of Nuclear Medicine and Minnan PET Center, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China. Department of Radiation Oncology, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China. (4) Department of Oncology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China. (5) Laboratory of Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China. (6) Department of Nuclear Medicine and Minnan PET Center, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China. (7) Department of Nuclear Medicine and Minnan PET Center, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China. (8) Department of Radiation Oncology, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China. (9) Department of Colorectal Tumor Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China leochen0821@foxmail.com wzhaoliang01@163.com chen.shawn@nus.edu.sg suguoqiang66@163.com. (10) Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore leochen0821@foxmail.com wzhaoliang01@163.com chen.shawn@nus.edu.sg suguoqiang66@163.com. Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), Singapore. (11) Department of Nuclear Medicine and Minnan PET Center, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China leochen0821@foxmail.com wzhaoliang01@163.com chen.shawn@nus.edu.sg suguoqiang66@163.com. (12) Department of Nuclear Medicine and Minnan PET Center, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China leochen0821@foxmail.com wzhaoliang01@163.com chen.shawn@nus.edu.sg suguoqiang66@163.com.
Citation: J Immunother Cancer 2025 Jan 11 13: Epub01/11/2025
