肿瘤细胞治疗研究
英文原题：Reduction of primary tumor growth and metastasis in models of triple-negative breast cancer following tilorone administration via type I interferon signaling.
Reduction of primary tumor growth and metastasis in models of triple-negative breast cancer following tilorone administration via type I interferon signaling.
这些数据共同支持 tilorone 及其他 IFN 信号诱导剂可增强化疗药物的效果，从而用于治疗转移性乳腺癌。
背景：三阴性乳腺癌（TNBC）患者的生存通常差于其他乳腺癌亚型，可选治疗也更少。已有研究指出，I 型干扰素（IFN）信号是 TNBC 转移和治疗反应的重要调节因素，但 IFN 疗法的脱靶毒性限制了其临床应用。增强骨形态发生蛋白（BMP）信号也与抗转移作用相关，但目前 BMP 疗法尚未用于临床。Tilorone 是一种可诱导 IFN 信号的抗病毒药物，近期也受到关注，因为它还能增强 BMP 信号。鉴于 tilorone 可增强这两种关注机制，研究者在转移性乳腺癌临床前模型中评估其治疗效果。 方法：采用多种体外实验研究 tilorone 对 4T1.2、EMT6.5、TBCP-1 和 MDA-MB-231-HM 细胞的作用。在原位 4T1.2 乳腺肿瘤小鼠中，该模型为 TNBC 的同系转移模型；研究通过 qPCR 比较是否给予 tilorone 时的转移负荷，并采用非配对 t 检验。另以双因素方差分析检验 tilorone 与 4 mg/kg 多柔比星联用的作用。 结果：在 4T1.2 细胞中，tilorone 增加 IFN 刺激基因（ISG）的表达，也降低肺转移负荷。缺乏 IFN 受体（IFNAR1）的小鼠中，tilorone 相关的生存改善减弱。研究进一步考察了 tilorone 与多柔比星联用的抗转移作用。在接受多柔比星的 4T1.2 肿瘤小鼠中，联合 tilorone 可提高原发肿瘤内 NK 细胞成熟度，并增强转移前肺组织中的 CD4⁺、CD8⁺ T 细胞活化和 NK 细胞成熟，从而延长无转移生存。患者数据分析发现，TNBC 肿瘤中 ISG 高表达与总生存延长相关，但其他乳腺癌亚型中未见这一关联。此外，与化疗无应答患者相比，化疗应答 TNBC 患者的肿瘤中多数 ISG 表达更高。 结论：总体而言，数据支持使用 tilorone 等 IFN 信号诱导剂增强化疗药物对转移性乳腺癌的治疗作用。
BACKGROUND: People with triple-negative breast cancer (TNBC) typically have poorer survival than those with other breast cancer subtypes, with fewer treatment options available. Type I interferon (IFN) signaling has been reported as an important regulator of metastasis and therapeutic response in TNBC, but the off-target toxicity of IFN therapies has limited progression to clinical use. Augmenting Bone Morphogenetic Protein (BMP) signaling has also been associated with anti-metastatic effects, but BMP therapies are not clinically available presently. Tilorone is an anti-viral drug that induces IFN signaling, which has recently gained added attention as an enhancer of BMP signaling. As an agent capable of enhancing two mechanisms of interest, we therefore aimed to test the therapeutic effects of tilorone in preclinical models of metastatic breast cancer. METHODS: The effect of tilorone on 4T1.2, EMT6.5, TBCP-1 and MDA-MB-231-HM cells was studied using multiple in vitro assays. We also compared metastatic burden by qPCR in mice bearing orthotopic 4T1.2 mammary tumors - a syngeneic and metastatic model of TNBC - with and without tilorone by unpaired t-tests. The effect of tilorone in combination with 4 mg/kg doxorubicin was tested by a 2-way ANOVA. RESULTS: In 4T1.2 cells, tilorone increased expression of IFN stimulated genes (ISGs). Tilorone also reduced lung metastatic burden. Improvements in survival associated with tilorone administration were blunted in mice that lacked the IFN / receptor (IFNAR1). The anti-metastatic impact of tilorone was further examined in combination with doxorubicin. In mice bearing 4T1.2 tumors, and receiving doxorubicin, co-treatment with tilorone increased natural killer (NK) cell maturation in the primary tumor, increased CD4 + & CD8 + T cell activation and NK cell maturation in the pre-metastatic lung, and enhanced metastasis-free survival. Analysis of patient data identified high ISG gene expression in tumors correlated with increased overall survival in TNBC but not in patients with other breast cancer subtypes. Additionally, most ISGs were more highly expressed in the tumors of TNBC patients who responded to chemotherapy, compared to non-responders. CONCLUSIONS: Collectively, the data support the utility of tilorone and other inducers of IFN signaling to enhance the effects of chemotherapeutic drugs for treating metastatic breast cancers.
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