GFRAL-Fc disarms GDF15 to reprogram tumor immunity and amplify PD-1 efficacy in hepatocellular carcinoma.

IF 8.2 2区 生物学 Q1 CELL BIOLOGY
Gege Shi, Wangqian Zhang, Fei Xie, Jiaxin Shi, Minghui Yan, Lei He, Zhaozhao Li, Yang Xiao, Duo Yu, Haiyan Cao, Haichen Du, Yueyuan Qiu, Kuo Zhang, Shuning Wang, Meng Li, Jieyu Zhang, Zhaowei Wang
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引用次数: 0

Abstract

Background: Checkpoint inhibitors have revolutionized hepatocellular carcinoma (HCC) treatment, yet their efficacy remains limited in advanced stages, with suboptimal objective response rates. Growth differentiation factor 15 (GDF15), a dual-functional cytokine implicated in tumor progression and immunosuppression, represents a promising therapeutic target. This study aims to develop a novel GDF15-targeted strategy to improve HCC management and synergize with PD-1 blockade.

Methods: GFRAL-Fc fusion proteins were generated by fusing the extracellular domain of GFRAL with IgG1 Fc. The anti-tumor efficacy and the anti-cachexia ability of GFRAL-Fc was evaluated in a spontaneous HCC model on GDF15 humanized mice. Additionally, the half-life and drug safety were evaluated in mice. To investigate the underlying mechanisms, a CyTOF analysis was utilized to analysis the immunoregulation effects of GFRAL-Fc within HCC. Finally, the anti-tumor effects of GFRAL-Fc in combination with Programmed Death-1 (PD-1) inhibitors were assessed.

Results: GFRAL-Fc targets GDF15 to simultaneously prevent GDF15-CD48 interaction-driven ERK activation and block GDF15-GFRAL binding. Treatment with GFRAL-Fc achieved dual antitumor effects: reducing tumor progression and attenuating cancer-associated cachexia. Combination with PD-1 blockade further enhanced antitumor efficacy, resulting in a substantial decrease in tumor nodules. Mechanistic studies revealed that GFRAL-Fc reprograms the immunosuppressive tumor microenvironment by suppressing Treg activation while enhancing CD8+ T cell cytotoxicity.

Conclusions: Our findings validate GDF15 targeting as a viable strategy to overcome checkpoint inhibitor resistance in HCC. The GFRAL-Fc fusion protein demonstrates multimodal therapeutic benefits through metabolic regulation and immune remodeling, providing a clinically translatable approach to optimize PD-1-based regimens. This study addresses critical gaps in current HCC management and warrants further clinical validation.

GFRAL-Fc解除GDF15的武装,重编程肿瘤免疫,增强PD-1在肝细胞癌中的疗效。
背景:检查点抑制剂已经彻底改变了肝细胞癌(HCC)的治疗,但其在晚期的疗效仍然有限,客观缓解率不理想。生长分化因子15 (GDF15)是一种涉及肿瘤进展和免疫抑制的双功能细胞因子,是一种很有前景的治疗靶点。本研究旨在开发一种新的靶向gdf15的策略来改善HCC的管理并与PD-1阻断协同。方法:将GFRAL的胞外结构域与IgG1 Fc融合生成GFRAL-Fc融合蛋白。在GDF15人源化小鼠自发性HCC模型中评价GFRAL-Fc的抗肿瘤功效和抗恶病质能力。并对其在小鼠体内的半衰期和用药安全性进行了评价。为了研究其潜在的机制,我们使用了CyTOF分析来分析GFRAL-Fc在HCC中的免疫调节作用。最后,评估GFRAL-Fc联合程序性死亡-1 (PD-1)抑制剂的抗肿瘤作用。结果:GFRAL-Fc靶向GDF15,同时阻止GDF15- cd48相互作用驱动的ERK活化,阻断GDF15- gfral结合。GFRAL-Fc治疗具有双重抗肿瘤作用:减少肿瘤进展和减轻癌症相关的恶病质。联合PD-1阻断进一步增强抗肿瘤疗效,使肿瘤结节显著减少。机制研究表明,GFRAL-Fc通过抑制Treg激活,同时增强CD8+ T细胞的细胞毒性,对免疫抑制的肿瘤微环境进行重编程。结论:我们的研究结果验证了GDF15靶向治疗是克服HCC中检查点抑制剂耐药的可行策略。GFRAL-Fc融合蛋白通过代谢调节和免疫重塑显示出多种模式的治疗益处,为优化基于pd -1的方案提供了一种临床可翻译的方法。该研究解决了当前HCC管理的关键空白,并需要进一步的临床验证。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
11.00
自引率
0.00%
发文量
180
期刊介绍: Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.
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