免疫原性
放射性配体
多塔
靶向治疗
医学
药理学
放射化学
癌症研究
化学
内科学
癌症
免疫学
受体
抗体
螯合作用
有机化学
作者
Jian‐Hao Chen,Yangfan Zhou,Yizhen Pang,Kaili Fu,Qicong Luo,Long Sun,Hua Wu,Qin Lin,Guoqiang Su,Xiaoyuan Chen,Liang Zhao,Haojun Chen
标识
DOI:10.1136/jitc-2024-010212
摘要
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 (αPD-L1 mAb). Notably, the combination of 177 Lu-DOTA-2P(FAPI) 2 with αPD-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 αPD-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.
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