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Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. ​

文献信息 ​

DOI10.1126/science.1240527
PMID24264989
期刊Science (New York, N.Y.)
影响因子45.8
JCR 分区Q1
发表年份2013
被引次数1157
关键词共生细菌, 肿瘤微环境, 免疫疗法, 化疗, 炎症
文献类型Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't
ISSN0036-8075
页码967-70
期号342(6161)
作者Noriho Iida, Amiran Dzutsev, C Andrew Stewart, Loretta Smith, Nicolas Bouladoux, Rebecca A Weingarten, Daniel A Molina, Rosalba Salcedo, Timothy Back, Sarah Cramer, Ren-Ming Dai, Hiu Kiu, Marco Cardone, Shruti Naik, Anil K Patri, Ena Wang, Francesco M Marincola, Karen M Frank, Yasmine Belkaid, Giorgio Trinchieri, Romina S Goldszmid

一句话小结 ​

本研究探讨了肠道微生物群对肿瘤微环境中炎症的影响，发现微生物群的破坏会显著降低皮下肿瘤对免疫治疗和化疗的反应，导致治疗效果不佳。研究结果强调了维持完整共生微生物群在癌症治疗中的重要性，提示其可能通过调节髓源细胞功能来影响治疗结果。

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共生细菌 · 肿瘤微环境 · 免疫疗法 · 化疗 · 炎症

摘要 ​

肠道微生物群影响局部和全身性炎症。炎症在癌症的发展、进展和治疗中起着重要作用，但尚不清楚共生细菌是否会影响无菌肿瘤微环境中的炎症。我们的研究表明，微生物群的破坏会削弱皮下肿瘤对CpG寡核苷酸免疫治疗和铂类化疗的反应。在接受抗生素处理或无菌小鼠中，肿瘤浸润的髓源细胞对治疗反应不佳，导致CpG寡核苷酸治疗后细胞因子产生减少及肿瘤坏死，化疗后反应性氧种和细胞毒性产生不足。因此，癌症治疗的最佳反应需要完整的共生微生物群，它通过调节肿瘤微环境中髓源细胞的功能来发挥作用。这些发现强调了微生物群在疾病治疗结果中的重要性。

英文摘要 ​

The gut microbiota influences both local and systemic inflammation. Inflammation contributes to development, progression, and treatment of cancer, but it remains unclear whether commensal bacteria affect inflammation in the sterile tumor microenvironment. Here, we show that disruption of the microbiota impairs the response of subcutaneous tumors to CpG-oligonucleotide immunotherapy and platinum chemotherapy. In antibiotics-treated or germ-free mice, tumor-infiltrating myeloid-derived cells responded poorly to therapy, resulting in lower cytokine production and tumor necrosis after CpG-oligonucleotide treatment and deficient production of reactive oxygen species and cytotoxicity after chemotherapy. Thus, optimal responses to cancer therapy require an intact commensal microbiota that mediates its effects by modulating myeloid-derived cell functions in the tumor microenvironment. These findings underscore the importance of the microbiota in the outcome of disease treatment.

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主要研究问题 ​

  1. 如何评估肠道微生物群在不同类型癌症治疗中的作用？
  2. 除了肠道微生物群，是否还有其他因素影响肿瘤微环境的免疫反应？
  3. 在抗生素治疗期间，肠道微生物的变化对癌症治疗结果的影响是什么？
  4. 目前有哪些方法可以用来恢复或增强肠道微生物群以改善癌症治疗效果？
  5. 不同的肠道微生物群组成是否会影响患者对免疫疗法的反应差异？

核心洞察 ​

研究背景和目的 ​

肠道微生物群在代谢、组织发育、炎症和免疫中发挥重要作用。研究表明，微生物群可能影响肿瘤微环境中的炎症反应，从而影响癌症的发展和治疗反应。本研究旨在探讨共生细菌如何通过调节肿瘤微环境来控制癌症对治疗的反应。

主要方法/材料/实验设计 ​

本研究采用小鼠模型，使用抗生素混合物（ABX）处理小鼠，以干扰肠道微生物群。选择了三种肿瘤类型（EL4淋巴瘤、MC38结肠癌和B16黑色素瘤）进行研究。实验流程如下：

Mermaid diagram
  1. 小鼠处理：在肿瘤接种前3周开始口服抗生素，持续至实验结束。
  2. 肿瘤接种：在小鼠皮下接种肿瘤细胞，监测肿瘤生长。
  3. 治疗评估：使用CpG-ODN和抗IL-10R抗体进行免疫治疗，使用铂类药物进行化疗。
  4. 结果分析：评估肿瘤体积、细胞因子水平和肿瘤坏死情况。

关键结果和发现 ​

  • 抗生素处理小鼠在CpG-ODN免疫治疗和铂类化疗中表现出较差的肿瘤反应，肿瘤坏死和细胞因子生成显著降低。
  • 在ABX处理的小鼠中，肿瘤内浸润的髓源细胞的功能受损，表现为TNF生成减少和细胞毒性降低。
  • 微生物群的完整性对肿瘤的免疫反应至关重要，肠道细菌通过调节髓源细胞的功能影响肿瘤微环境。

主要结论/意义/创新性 ​

本研究首次揭示了肠道微生物群通过影响髓源细胞的功能来调节肿瘤微环境和癌症治疗反应的重要性。这一发现为癌症治疗提供了新的思路，表明通过调节肠道微生物群可能提高癌症治疗的效果。

研究局限性和未来方向 ​

  • 本研究主要基于小鼠模型，未来需要在人类中验证这些发现。
  • 研究未能深入探讨不同细菌种类对肿瘤反应的具体影响，未来可针对特定细菌进行研究。
  • 需要探索微生物群的改变如何影响不同类型的癌症和治疗方式，以制定个性化的治疗策略。

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引用本文的文献 ​

  1. Tumour immunology: Anticancer drugs need bugs. - Yvonne Bordon - Nature reviews. Immunology (2014)
  2. Chemotherapy, immunity and microbiota--a new triumvirate? - Michael Karin;Christian Jobin;Frances Balkwill - Nature medicine (2014)
  3. Tumour microenvironment: bacterial balance affects cancer treatment. - Isabel Lokody - Nature reviews. Cancer (2014)
  4. Host immune response to infection and cancer: unexpected commonalities. - Romina S Goldszmid;Amiran Dzutsev;Giorgio Trinchieri - Cell host & microbe (2014)
  5. Microbes, microbiota, and colon cancer. - Cynthia L Sears;Wendy S Garrett - Cell host & microbe (2014)
  6. The intestinal metabolome: an intersection between microbiota and host. - Luke K Ursell;Henry J Haiser;Will Van Treuren;Neha Garg;Lavanya Reddivari;Jairam Vanamala;Pieter C Dorrestein;Peter J Turnbaugh;Rob Knight - Gastroenterology (2014)
  7. Mechanistic insight into digoxin inactivation by Eggerthella lenta augments our understanding of its pharmacokinetics. - Henry J Haiser;Kristen L Seim;Emily P Balskus;Peter J Turnbaugh - Gut microbes (2014)
  8. Nucleoside-catabolizing enzymes in mycoplasma-infected tumor cell cultures compromise the cytostatic activity of the anticancer drug gemcitabine. - Johan Vande Voorde;Suna Sabuncuoğlu;Sam Noppen;Anders Hofer;Farahnaz Ranjbarian;Steffen Fieuws;Jan Balzarini;Sandra Liekens - The Journal of biological chemistry (2014)
  9. Role of the microbiota in immunity and inflammation. - Yasmine Belkaid;Timothy W Hand - Cell (2014)
  10. Individualized medicine from prewomb to tomb. - Eric J Topol - Cell (2014)

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