FAP-targeted Radioligand Therapy with Ga/Lu-DOTA-2P(FAPI) Enhance Immunogenicity and Synergize with PD-L1 Inhibitors for Improved Antitumor Efficacy

Overview

Journal J Immunother Cancer

Date 2025 Jan 12

PMID 39800373

Authors

Jianhao Chen

Yangfan Zhou

Yizhen Pang

Kaili Fu

Qicong Luo

Long Sun

Hua Wu

Qin Lin

Guoqiang Su

Xiaoyuan Chen

Liang Zhao

Haojun Chen

Affiliations

Soon will be listed here.

Abstract

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, Ga/Lu-DOTA-2P(FAPI), 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 Ga/Lu-DOTA-2P(FAPI) 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 Ga and Lu labeled DOTA-2P(FAPI), respectively. Monotherapy with Ga-DOTA-2P(FAPI), Lu-DOTA-2P(FAPI), and PD-L1 immunotherapy as well as combination therapy (Ga/Lu-DOTA-2P(FAPI) 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 Lu-DOTA-2P(FAPI) proving to be more effective than Ga-DOTA-2P(FAPI). Both Ga-DOTA-2P(FAPI) and Lu-DOTA-2P(FAPI) radiopharmaceuticals significantly improved therapeutic outcomes when combined with anti-PD-L1 monoclonal antibody (αPD-L1 mAb). Notably, the combination of Lu-DOTA-2P(FAPI) 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 Lu-DOTA-2P(FAPI) 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 Lu-DOTA-2P(FAPI), 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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