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
ProAgio，一种新型整合素αvβ3 靶向细胞毒素，抑制肿瘤生长并重编程 PDAC 微环境
英文原题：ProAgio, a Novel Integrin αvβ3 Targeted Cytotoxin, Suppresses Tumor Growth and Reprograms the PDAC Microenvironment.
查看英文原题
ProAgio, a Novel Integrin αvβ3 Targeted Cytotoxin, Suppresses Tumor Growth and Reprograms the PDAC Microenvironment.
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研究概要
使用 ProAgio 靶向整合素αvβ3 通过改善灌注、减少缺氧、逆转 EMT 和减轻免疫抑制来调节 PDAC TME。ProAgio 增强了 GPH 疗法的效果，应在未来试验中进行评估。
研究思路结论见上方概要
背景
胰腺导管腺癌（PDAC）的特征是致密、缺氧和免疫抑制的肿瘤微环境（TME）。表达整合素αvβ3的细胞，包括内皮细胞和癌相关成纤维细胞（CAFs），参与该TME的形成。ProAgio是一种新型细胞毒素，靶向表达整合素αvβ3的细胞。ProAgio目前正在进行临床试验。我们此前已表明，GPH（吉西他滨、帕立骨化醇和羟氯喹）联合方案可影响PDAC TME。基于作用机制的重叠，我们假设ProAgio可增强GPH的效果并增强其抗肿瘤免疫。
方法
患者来源的异种移植（PDX）和PDAC原位模型用于评估ProAgio联合GPH的治疗活性和作用机制。免疫组织化学用于评估缺氧、EMT和血管生成。免疫细胞的变化通过多参数流式细胞术测量。动态对比增强MRI（DCE-MRI）用于研究小鼠和患者的肿瘤灌注（NCT06182072）。
结果
ProAgio通过清除表达整合素β3的细胞，增强了GPH在PDX和原位模型中的生长抑制效果，导致ECM重塑、血管渗漏减少、缺氧改善以及EMT逆转。DCE-MRI显示，在小鼠和患者中，ProAgio治疗后肿瘤灌注显著增加（NCT06182072）。免疫分析显示，联合治疗显著增加了γδ T细胞、自然杀伤T（NKT）细胞、CD4+效应T细胞和M1样巨噬细胞的浸润。此外，联合治疗降低了肌成纤维细胞性CAFs（myCAFs）的表达，进一步支持了GPH和ProAgio的免疫调节和基质正常化作用。
展开英文摘要原文
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense, hypoxic and immune-suppressive tumor microenvironment (TME). Integrin αvβ3-expressing cells, including endothelial and cancer-associated fibroblasts (CAFs), contribute to the development of this TME. ProAgio is a novel cytotoxin that targets integrin αvβ3-expressing cells. ProAgio is currently in clinical trials. We have previously shown that the combination of GPH (gemcitabine, paricalcitol, and hydroxychloroquine) influences PDAC TME. Based on the overlapping mechanisms of action, we hypothesized that ProAgio could potentiate effects of GPH and enhance its anti-tumor immunity.
METHODS
Patient-derived xenograft (PDX) and orthotopic models of PDAC were used to assess the therapeutic activity and mechanism of action of ProAgio in combination with GPH. Immunohistochemistry was used to evaluate hypoxia, EMT and angiogenesis. Changes in the immune cells were measured with multi-parameter flow cytometry. Dynamic contrast-enhanced MRI (DCE-MRI) was used to study tumor perfusion in mice and patients (NCT06182072).
FINDINGS
ProAgio potentiated the growth inhibitory effects of GPH in PDX and orthotopic models by depleting integrin β3 expressing cells, leading to ECM remodeling, reduced vascular leakage, improved hypoxia, and reversed EMT. DCE-MRI showed a significant increase in tumor perfusion following ProAgio treatment in mice and patients (NCT06182072). Immune profiling revealed that the combination treatment significantly increased the infiltration of γδ T cells, natural killer T (NKT) cells, CD4 + effector T cells, and M1-like macrophages. Furthermore, the combination treatment reduced the expression of myofibroblastic CAFs (myCAFs), further supporting the immunomodulatory and stromal normalizing effects of GPH and ProAgio.
CONCLUSION
Targeting integrin αvβ3 using ProAgio modulates the PDAC TME by improving perfusion, reducing hypoxia, reversing EMT, and alleviating immune suppression. ProAgio potentiates the effects of GPH therapy, which should be evaluated in future trials.
论文信息
- 作者
- Bandi DSR、Sarvesh S、Nagaraju GP、Kim H、Foote J、Bae S、Yoon KJ、Malla M
- 单位
- Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.United States
- 文献类型
- 预印本
- 期刊
- bioRxiv : the preprint server for biology2026 Jan 16
- 原文标识
- PubMed 41648362 · DOI 10.64898/2026.01.15.699725