信号转导和转录激活因子3（STAT3）抑制与CD47阻断联合使用可抑制骨肉瘤肺转移。

STAT3 inhibition in combination with CD47 blockade inhibits osteosarcoma lung metastasis.

作者信息

Shrestha Pradeep, Shrestha Rejeena, Zhou You, Zielinski Rafal, Priebe Waldemar, Kleinerman Eugenie S

机构信息

Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

出版信息

Front Immunol. 2025 Jun 3;16:1608375. doi: 10.3389/fimmu.2025.1608375. eCollection 2025.

DOI:10.3389/fimmu.2025.1608375

PMID:40529368

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12170595/

Abstract

BACKGROUND

New therapies are urgently needed for patients with osteosarcoma (OS). STAT3 and CD47 are potential therapeutic target in OS. Here we investigated the therapeutic activity of the orally bioavailable STAT3 inhibitor, WP1066, and anti-CD47 antibody using OS mouse models.

METHODS

Cytotoxic effect of WP1066 against OS cell lines and its immunomodulatory effects were evaluated . Experimental metastasis and orthotopic syngeneic mouse models were used to investigate the therapeutic efficacy of WP1066 and anti-CD47 antibody. Further flow cytometric analysis was performed.

RESULTS

STAT3 was constitutively activated in multiple human and mouse OS cell lines. WP1066 suppressed STAT3 activation and induced apoptosis. WP1066 reduced the viability and proliferation of MDSCs and increased the expression level of MHC-II, and CD80 in macrophages. We demonstrated that WP1066 monotherapy prolonged the survival of mice with OS lung metastasis using an experimental metastasis and an orthotopic model. The therapeutic effect was significantly increased when WP1066 was combined with anti-CD47. This was associated with increased frequency of activated CD8 T cells, NK cells and macrophages in the lungs and LDLNs.

CONCLUSION

Our preclinical studies support further investigation of targeting STAT3 and CD47 as novel immunotherapeutic approach against OS lung metastasis.

摘要

背景

骨肉瘤（OS）患者迫切需要新的治疗方法。STAT3和CD47是骨肉瘤潜在的治疗靶点。在此，我们使用骨肉瘤小鼠模型研究了口服生物利用度高的STAT3抑制剂WP1066和抗CD47抗体的治疗活性。

方法

评估WP1066对骨肉瘤细胞系的细胞毒性作用及其免疫调节作用。使用实验性转移和原位同基因小鼠模型研究WP1066和抗CD47抗体的治疗效果。进一步进行流式细胞术分析。

结果

STAT3在多种人和小鼠骨肉瘤细胞系中持续激活。WP1066抑制STAT3激活并诱导细胞凋亡。WP1066降低了骨髓来源抑制细胞（MDSCs）的活力和增殖，并增加了巨噬细胞中MHC-II和CD80的表达水平。我们证明，使用实验性转移和原位模型，WP1066单药治疗可延长骨肉瘤肺转移小鼠的生存期。当WP1066与抗CD47联合使用时，治疗效果显著增强。这与肺和局部引流淋巴结（LDLNs）中活化的CD8 T细胞、自然杀伤细胞（NK细胞）和巨噬细胞频率增加有关。