Combination Therapy of TGF-β Blockade and Commensal-derived Probiotics Provides Enhanced Antitumor Immune Response and Tumor Suppression.,Theranostics

当前位置： X-MOL 学术 › Theranostics › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Combination Therapy of TGF-β Blockade and Commensal-derived Probiotics Provides Enhanced Antitumor Immune Response and Tumor Suppression.
Theranostics ( IF 12.4 ) Pub Date : 2019-01-01 , DOI: 10.7150/thno.35131
Linlin Shi ₁ , Jianyong Sheng ₁ , Mengli Wang ₂ , Han Luo ₁ , Jun Zhu _{3,

4} , Bixiang Zhang ₅ , Zhi Liu ₃ , Xiangliang Yang ₁

Affiliation

Galunisertib (Gal) is a transforming growth factor (TGF-β) blockade which is being investigated as a potential tumor immunotherapy candidate drug in clinical trials. However, primary or acquired resistance is often found in the recruited cancer patients, which limits its clinical application. Tumor immune microenvironment can be regulated by intestinal microbiota, leading to different therapeutic outcomes. It is hypothesized that manipulation of cancer patients' intestinal microbiome in the early stage of therapy may be a promising strategy to improve the therapeutic efficacy of Gal. Methods: 4T1 and H22 subcutaneous tumor bearing mice were used to evaluate the therapeutic effect. Escherichia coli strain Nissle 1917 (EcN), a widely used probiotic bacteria, was orally delivered to the tumor bearing mice daily along with Gal treatment. Antitumor effect of the combination therapy was evaluated by tumor volume, histological staining of tumor tissues. Furthermore, flow cytometry was performed to analyze the alteration of immune microenvironment in tumor bed after treatment. The suppressing effect of the combination therapy on tumor invasiveness and metastasis was evaluated in both mice and zebrafish xenografts models. Fecal sample 16S rRNA gene sequencing was conducted to analyze changes of intestinal microbial diversity. The effect of intestinal microbiota on tumor suppression after receiving EcN was further tested by fecal transplant. Results: The therapeutic outcomes in tumor growth inhibition and metastasis suppression of Gal were significantly potentiated by EcN, resulting from the strengthened antitumor immunity. EcN was able to relieve the immunosuppressive tumor microenvironment, which was evidenced by enhanced tumor-specific effector T cells infiltration and dendritic cells activation. Intestinal microbiota was modulated by EcN, illustrated by a shift of gut microbiome toward certain beneficial bacteria. Conclusion: These results suggested that Gal combined with EcN might be a novel therapeutic approach with great potential of clinical implications for cancer prevention or treatment.

中文翻译：

TGF-β 阻断剂和共生源益生菌的联合治疗可增强抗肿瘤免疫反应和肿瘤抑制。

Galunisertib (Gal) 是一种转化生长因子 (TGF-β) 阻断剂，正在临床试验中作为潜在的肿瘤免疫治疗候选药物进行研究。然而，在招募的癌症患者中经常发现原发性或获得性耐药，这限制了其临床应用。肿瘤免疫微环境可以通过肠道微生物群进行调节，从而导致不同的治疗结果。据推测，在治疗的早期阶段控制癌症患者的肠道微生物组可能是提高 Gal 治疗效果的一个有前途的策略。方法：采用4T1和H22皮下荷瘤小鼠评价治疗效果。大肠杆菌菌株 Nissle 1917 (EcN) 是一种广泛使用的益生菌，每天与 Gal 治疗一起口服给荷瘤小鼠。通过肿瘤体积、肿瘤组织的组织学染色评价联合治疗的抗肿瘤效果。此外，通过流式细胞术分析治疗后瘤床免疫微环境的变化。在小鼠和斑马鱼异种移植模型中评估了联合疗法对肿瘤侵袭和转移的抑制作用。对粪便样本进行16S rRNA基因测序，分析肠道微生物多样性的变化。通过粪便移植进一步测试了接受 EcN 后肠道微生物群对肿瘤抑制的作用。结果：EcN 增强了抗肿瘤免疫力，显着增强了 Gal 的肿瘤生长抑制和转移抑制的治疗效果。 EcN 能够缓解免疫抑制的肿瘤微环境，增强的肿瘤特异性效应 T 细胞浸润和树突状细胞激活证明了这一点。肠道微生物群受到 EcN 的调节，肠道微生物群向某些有益细菌的转变就说明了这一点。结论：这些结果表明 Gal 联合 EcN 可能是一种新的治疗方法，对癌症预防或治疗具有巨大的临床意义。

更新日期：2019-01-01

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11