Christophe Gattlen PhD , Kirby R. Frank MSc , Damien N. Marie MSc , Aurélien Trompette MSc , Louis-Emmanuel Chriqui MD, PhD , Yameng Hao PhD , Etienne Abdelnour MD , Michel Gonzalez MD , Thorsten Krueger MD , Paul J. Dyson PhD , Sviatlana Siankevich PhD , Christophe von Garnier MD , Niki D.J. Ubags PhD , Sabrina Cavin PhD , Jean Y. Perentes MD, PhD
{"title":"使用新型微生物组调节剂提高鼠恶性胸膜间皮瘤模型的抗癌免疫力","authors":"Christophe Gattlen PhD , Kirby R. Frank MSc , Damien N. Marie MSc , Aurélien Trompette MSc , Louis-Emmanuel Chriqui MD, PhD , Yameng Hao PhD , Etienne Abdelnour MD , Michel Gonzalez MD , Thorsten Krueger MD , Paul J. Dyson PhD , Sviatlana Siankevich PhD , Christophe von Garnier MD , Niki D.J. Ubags PhD , Sabrina Cavin PhD , Jean Y. Perentes MD, PhD","doi":"10.1016/j.xjon.2024.02.007","DOIUrl":null,"url":null,"abstract":"<div><h3>Objective</h3><p>Malignant pleural mesothelioma is a fatal disease and a clinical challenge, as few effective treatment modalities are available. Previous evidence links the gut microbiome to the host immunoreactivity to tumors. We thus evaluated the impact of a novel microbiome modulator compound (MMC) on the gut microbiota composition, tumor immune microenvironment, and cancer control in a model of malignant pleural mesothelioma.</p></div><div><h3>Methods</h3><p>Age- and weight-matched immunocompetent (n = 23) or athymic BALB/c mice (n = 15) were randomly assigned to MMC or no treatment (control) groups. MMC (31 ppm) was administered through the drinking water 14 days before AB12 malignant mesothelioma cell inoculation into the pleural cavity. The impact of MMC on tumor growth, animal survival, tumor-infiltrating leucocytes, gut microbiome, and fecal metabolome was evaluated and compared with those of control animals.</p></div><div><h3>Results</h3><p>The MMC delayed tumor growth and significantly prolonged the survival of immunocompetent animals (<em>P</em> = .0015) but not that of athymic mice. The improved tumor control in immunocompetent mice correlated with increased infiltration of CD3<sup>+</sup>CD8<sup>+</sup>GRZB<sup>+</sup> cytotoxic T lymphocytes in tumors. Gut microbiota analyses indicated an enrichment in producers of short chain fatty acids in MMC-treated animals. Finally, we observed a positive correlation between the level of fecal short chain fatty acids and abundance of tumor-infiltrating cytotoxic T cells in malignant pleural mesothelioma.</p></div><div><h3>Conclusions</h3><p>MMC administration boosts antitumor immunity, which correlates with a change in gut microbiome and metabolome. 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引用次数: 0
摘要
目的 恶性胸膜间皮瘤是一种致命疾病，也是一项临床挑战，因为目前几乎没有有效的治疗方法。以往的证据表明，肠道微生物组与宿主对肿瘤的免疫反应有关。因此，我们评估了一种新型微生物组调节化合物（MMC）对恶性胸膜间皮瘤模型中肠道微生物组的组成、肿瘤免疫微环境和癌症控制的影响。在将 AB12 恶性间皮瘤细胞接种到胸膜腔前 14 天，通过饮用水给小鼠注射 MMC（31 ppm）。评估 MMC 对肿瘤生长、动物存活率、肿瘤浸润白细胞、肠道微生物组和粪便代谢组的影响，并与对照组动物进行比较。免疫功能正常小鼠肿瘤控制能力的提高与肿瘤中 CD3+CD8+GRZB+ 细胞毒性 T 淋巴细胞浸润增加有关。肠道微生物群分析表明，经 MMC 治疗的动物体内富含短链脂肪酸。最后，我们观察到恶性胸膜间皮瘤患者粪便中短链脂肪酸的水平与肿瘤浸润细胞毒性 T 细胞的数量呈正相关。MMC 可能是癌症患者结合免疫疗法的一种有价值的治疗选择。
Use of a novel microbiome modulator improves anticancer immunity in a murine model of malignant pleural mesothelioma
Objective
Malignant pleural mesothelioma is a fatal disease and a clinical challenge, as few effective treatment modalities are available. Previous evidence links the gut microbiome to the host immunoreactivity to tumors. We thus evaluated the impact of a novel microbiome modulator compound (MMC) on the gut microbiota composition, tumor immune microenvironment, and cancer control in a model of malignant pleural mesothelioma.
Methods
Age- and weight-matched immunocompetent (n = 23) or athymic BALB/c mice (n = 15) were randomly assigned to MMC or no treatment (control) groups. MMC (31 ppm) was administered through the drinking water 14 days before AB12 malignant mesothelioma cell inoculation into the pleural cavity. The impact of MMC on tumor growth, animal survival, tumor-infiltrating leucocytes, gut microbiome, and fecal metabolome was evaluated and compared with those of control animals.
Results
The MMC delayed tumor growth and significantly prolonged the survival of immunocompetent animals (P = .0015) but not that of athymic mice. The improved tumor control in immunocompetent mice correlated with increased infiltration of CD3+CD8+GRZB+ cytotoxic T lymphocytes in tumors. Gut microbiota analyses indicated an enrichment in producers of short chain fatty acids in MMC-treated animals. Finally, we observed a positive correlation between the level of fecal short chain fatty acids and abundance of tumor-infiltrating cytotoxic T cells in malignant pleural mesothelioma.
Conclusions
MMC administration boosts antitumor immunity, which correlates with a change in gut microbiome and metabolome. MMC may represent a valuable treatment option to combine with immunotherapy in patients with cancer.
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