RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
STAT3 抑制联合 CD47 阻断抑制骨肉瘤肺转移
英文原题：STAT3 inhibition in combination with CD47 blockade inhibits osteosarcoma lung metastasis.
查看英文原题
STAT3 inhibition in combination with CD47 blockade inhibits osteosarcoma lung metastasis.
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研究概要
我们的临床前研究支持进一步研究靶向 STAT3 和 CD47 作为对抗 OS 肺转移的新型免疫治疗方法。
研究思路结论见上方概要
背景
骨肉瘤（OS）患者迫切需要新的治疗方法。STAT3和CD47是OS的潜在治疗靶点。在此，我们利用OS小鼠模型研究了口服生物可利用的STAT3抑制剂WP1066和抗CD47抗体的治疗活性。
方法
评估了WP1066对OS细胞系的细胞毒性作用及其体外免疫调节效应。采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。进一步进行了流式细胞术分析。
结果
STAT3在多种人和小鼠OS细胞系中呈组成性激活。WP1066抑制STAT3激活并诱导凋亡。WP1066降低MDSC的活力和增殖，并增加巨噬细胞中MHC-II和CD80的表达水平。我们利用实验性转移模型和原位模型证明，WP1066单药治疗延长了OS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LDLN中活化CD8+ T细胞、NK细胞和巨噬细胞频率增加相关。
展开英文摘要原文
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 in vitro . 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.
论文信息
- 作者
- Shrestha P、Shrestha R、Zhou Y、Zielinski R、Priebe W、Kleinerman ES
- 单位
- Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.United States
- 期刊
- Frontiers in immunology2025
- 原文标识
- PubMed 40529368 · DOI 10.3389/fimmu.2025.1608375
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